Substituted acid derivatives useful as antidiabetic and antiobesity agents and method

ABSTRACT

Compounds are provided which have the structure 
                         
wherein Q is C or N, A is O or S, Z is O or a bond, X is CH or N and R 1 , R 2 , R 2a , R 2b , R 2c , R 3 , Y, x, m, and n are as defined herein, which compounds are useful as antidiabetic, hypolipidemic, and antiobesity agents.

This is a divisional application of application Ser. No. 10/655,876filed Sep. 5, 2003 now U.S. Pat. No. 7,084,162, which is a divisionalapplication of application Ser. No. 10/080,981 filed Feb. 22, 2002, nowU.S. Pat. No. 6,653,314, which is a continuation of application Ser. No.09/812,960 filed Mar. 20, 2001, now U.S. Pat. No. 6,414,002, which is acontinuation-in-part of U.S. application Ser. No. 09/664,598 filed Sep.18, 2000, now abandoned, which application takes priority from U.S.provisional application No. 60/155,400 filed Sep. 22, 1999.

FIELD OF THE INVENTION

The present invention relates to novel substituted acid derivativeswhich modulate blood glucose levels, triglyceride levels, insulin levelsand non-esterified fatty acid (NEFA) levels, and thus are particularlyuseful in the treatment of diabetes and obesity, and to a method fortreating diabetes, especially Type 2 diabetes, as well as hyperglycemia,hyperinsulinemia, hyperlipidemia, obesity, atherosclerosis and relateddiseases employing such substituted acid derivatives alone or incombination with another antidiabetic agent and/or a hypolipidemicagent.

DESCRIPTION OF THE INVENTION

In accordance with the present invention, substituted acid derivativesare provided which have the structure I

wherein x is 1, 2, 3 or 4; m is 1 or 2; n is 1 or 2;

Q is C or N;

A is O or S;

Z is O or a bond;

R¹ is H or alkyl;

X is CH or N;

R² is H, alkyl, alkoxy, halogen, amino or substituted amino;

R^(2a), R^(2b) and R^(2c) may be the same or different and are selectedfrom H, alkyl, alkoxy, halogen, amino or substituted amino;

R³ is H, alkyl, arylalkyl, aryloxycarbonyl, alkyloxycarbonyl,alkynyloxycarbonyl, alkenyloxycarbonyl, arylcarbonyl, alkylcarbonyl,aryl, heteroaryl, alkyl(halo)aryloxycarbonyl,alkyloxy(halo)aryloxy-carbonyl, cycloalkylaryloxycarbonyl,cycloalkyloxyaryloxycarbonyl, cycloheteroalkyl, heteroarylcarbonyl,heteroaryl-heteroarylalkyl, alkylcarbonylamino, arylcarbonylamino,heteroarylcarbonylamino, alkoxycarbonylamino, aryloxycarbonylamino,heteroaryloxycarbonylamino, heteroaryl-heteroarylcarbonyl,alkylsulfonyl, alkenylsulfonyl, heteroaryloxycarbonyl,cycloheteroalkyloxycarbonyl, heteroarylalkyl, aminocarbonyl, substitutedaminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylalkenyl,cycloheteroalkyl-heteroarylalkyl; hydroxyalkyl, alkoxy,alkoxyaryloxycarbonyl, arylalkyloxycarbonyl, alkylaryloxycarbonyl,arylheteroarylalkyl, arylalkylarylalkyl, aryloxyarylalkyl,haloalkoxyaryloxycarbonyl, alkoxycarbonylaryloxycarbonyl,aryloxyaryloxycarbonyl, arylsulfinylarylcarbonyl, arylthioarylcarbonyl,alkoxycarbonylaryloxycarbonyl, arylalkenyloxycarbonyl,heteroaryloxyarylalkyl, aryloxyarylcarbonyl,aryloxyarylalkyloxycarbonyl, arylalkenyloxycarbonyl, arylalkylcarbonyl,aryloxyalkyloxycarbonyl, arylalkylsulfonyl, arylthiocarbonyl,arylalkenylsulfonyl, heteroarylsulfonyl, arylsulfonyl, alkoxyarylalkyl,heteroarylalkoxycarbonyl, arylheteroarylalkyl, alkoxyarylcarbonyl,aryloxyheteroarylalkyl, heteroarylalkyloxyarylalkyl, arylarylalkyl,arylalkenylarylalkyl, arylalkoxyarylalkyl, arylcarbonylarylalkyl,alkylaryloxyarylalkyl, arylalkoxycarbonylheteroarylalkyl,heteroarylarylalkyl, arylcarbonylheteroarylalkyl,heteroaryloxyarylalkyl, arylalkenylheteroarylalkyl, arylaminoarylalkyl,aminocarbonylarylarylalkyl;

Y is CO₂R⁴ (where R⁴ is H or alkyl, or a prodrug ester) or Y is aC-linked 1-tetrazole, a phosphinic acid of the structureP(O)(OR^(4a))R⁵, (where R^(4a) is H or a prodrug ester, R⁵ is alkyl oraryl) or phosphonic acid of the structure P(O)(OR^(4a))₂, (where R^(4a)is H or a prodrug ester);

X¹ _(x), X¹ _(n) and X¹ _(m) which may also be referred to as (CH₂)_(x),(CH₂)_(n) and (CH₂)_(m), respectively, may be optionally substitutedwith 1, 2 or 3 substituents;

including all stereoisomers thereof, prodrug esters thereof, andpharmaceutically acceptable salts thereof, with the proviso that

where X is CH, A is O, Q is C, Z is O, and Y is CO₂R⁴, then R³ is otherthan H or alkyl containing 1 to 5 carbons in the normal chain.

Thus, compounds of formula I of the invention may have the structure

Preferred are compounds of formula I of the invention having thestructure

More preferred are compounds of formula I of the invention having thestructures

In the above compounds, it is most preferred that R^(2a) is alkoxy, butmore preferably H, Z is a bond, but more preferably O, X¹ _(x) or(CH₂)_(x) is CH₂, (CH₂)₂, (CH₂)₃, or

X¹ _(m) or (CH₂)m is CH₂, or

(where R_(a) is alkyl such as methyl, or alkenyl such as —CH₂—CH═CH₂ or

X¹ _(n) or (CH₂)_(n) is CH₂, R¹ is lower alkyl, preferably —CH₃, R² isH, R^(2a) is H, R⁴ is H, X is CH, and R³ is arylalkyloxycarbonyl,arylheteroarylalkyl, aryloxyarylalkyl, arylalkyl, aryloxycarbonyl,haloaryl-oxycarbonyl, alkoxyaryloxycarbonyl, alkylaryloxycarbonyl,aryloxyaryloxycarbonyl, heteroaryloxyarylalkyl, heteroaryloxycarbonyl,aryloxyarylcarbonyl, arylalkenyloxycarbonyl, cycloalkylaryloxycarbonyl,arylalkylarylcarbonyl, heteroaryl-heteroarylalkyl,cycloalkyloxyaryloxycarbonyl, heteroaryl-heteroarylcarbonyl,alkyloxyaryloxycarbonyl, arylalkylsulfonyl, arylalkenylsulfonyl,alkoxyarylalkyl, arylthiocarbonyl, cycloheteroalkylalkyloxycarbonyl,cycloheteroalkyloxycarbonyl, or polyhaloalkylaryloxy-carbonyl, whereinthe above preferred groups may be optionally substituted.

Preferred compounds of the invention include the following:

In addition, in accordance with the present invention, a method isprovided for treating diabetes, especially Type 2 diabetes, and relateddiseases such as insulin resistance, hyperglycemia, hyperinsulinemia,elevated blood levels of fatty acids or glycerol, hyperlipidemia,obesity, hypertriglyceridemia, inflammation, Syndrome X, diabeticcomplications, dysmetabolic syndrome, atherosclerosis, and relateddiseases wherein a therapeutically effective amount of a compound ofstructure I is administered to a human patient in need of treatment.

In addition, in accordance with the present invention, a method isprovided for treating early malignant lesions (such as ductal carcinomain situ of the breast and lobular carcinoma in situ of the breast),premalignant lesions (such as fibroadenoma of the breast and prostaticintraepithelial neoplasia (PIN), liposarcomas and various otherepithelial tumors (including breast, prostate, colon, ovarian, gastricand lung), irritable bowel syndrome, Crohn's disease, gastric ulceritis,and osteoporosis and proliferative diseases such as psoriasis, wherein atherapeutically effective amount of a compound of structure I isadministered to a human patient in need of treatment.

In addition, in accordance with the present invention, a method isprovided for treating diabetes and related diseases as defined above andhereinafter, wherein a therapeutically effective amount of a combinationof a compound of structure I and another type antidiabetic agent and/ora hypolipidemic agent, and/or lipid modulating agent and/or other typeof therapeutic agent, is administered to a human patient in need oftreatment.

In the above methods of the invention, the compound of structure I willbe employed in a weight ratio to the antidiabetic agent (depending uponits mode of operation) within the range from about 0.01:1 to about100:1, preferably from about 0.5:1 to about 10:1.

The conditions, diseases, and maladies collectively referenced to as“Syndrome X” or Dysmetabolic Syndrome are detailed in Johannsson J.Clin. Endocrinol. Metab., 82, 727-734 (1997) and other publications.

The term “diabetes and related diseases” refers to Type II diabetes,Type I diabetes, impaired glucose tolerance, obesity, hyperglycemia,Syndrome X, dysmetabolic syndrome, diabetic complications andhyperinsulinemia.

The conditions, diseases and maladies collectively referred to as“diabetic complications” include retinopathy, neuropathy andnephropathy, and other known complications of diabetes.

The term “other type(s) of therapeutic agents” as employed herein refersto one or more antidiabetic agents (other than compounds of formula I),one or more anti-obesity agents, and/or one or more lipid-loweringagents, one or more lipid modulating agents (includinganti-atherosclerosis agents), and/or one or more antiplatelet agents,one or more agents for treating hypertension, one or more anti-cancerdrugs, one or more agents for treating arthritis, one or moreanti-osteoporosis agents, one or more anti-obesity agents, one or moreagents for treating immunomodulatory diseases, and/or one or more agentsfor treating anorexia nervosa.

The term “lipid-modulating” agent as employed herein refers to agentswhich lower LDL and/or raise HDL and/or lower triglycerides and/or lowertotal cholesterol and/or other known mechanisms for therapeuticallytreating lipid disorders.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the formula I of the present invention may be preparedaccording to the following general synthetic schemes, as well asrelevant published literature procedures that are used by one skilled inthe art. Exemplary reagents and procedures for these reactions appearhereinafter and in the working Examples. Protection and deprotection inthe Schemes below may be carried out by procedures generally known inthe art (see, for example, Greene, T. W. and Wuts, P. G. M., ProtectingGroups in Organic Synthesis, 3^(rd) Edition, 1999 [Wiley]).

Scheme 1 describes a general synthesis of the amino acids described inthis invention. An alcohol II (R⁵(CH₂)_(x)OH) (of which the most favoredis 2-phenyl-5-methyl-oxazole-4-ethanol) is coupled with a hydroxy aryl-or heteroaryl-aldehyde III (preferably 3- or 4-hydroxybenzaldehyde)under standard Mitsunobu reaction conditions (e.g. Mitsunobu, O.,Synthesis, 1981, 1). The resulting aldehyde IV is then subjected toreductive amination using procedures known in the literature (e.g.Abdel-Magid et al, J. Org. Chem. 1996, 61, 3849) with an α-amino esterhydrochloride V. PG in Scheme 1 denotes a preferred carboxylic acidprotecting group, such as a methyl or tert-butyl ester. The resultingsecondary amino-ester VI is then subjected to a second reductiveamination using methods known in the literature (e.g. Abdel-Magid et al,J. Org. Chem. 1996, 61, 3849) with an R^(3a) aldehyde VII. Finaldeprotection of the carboxylic acid ester under standard conditionsknown in the literature (Greene) utilizing basic conditions (for methylesters) or acidic conditions (for tert-butyl esters) then furnishes thedesired amino acid products ID.

An alternative route to the aldehyde IV is shown in Scheme 1A. Thealcohol II (R⁵(CH₂)_(x)OH) (of which the most favored is2-[2-phenyl-5-methyl-oxazole-4-yl]-ethanol) is treated withmethanesulfonyl chloride to give the corresponding mesylate VIII. Themesylate is then alkylated under standard basic conditions with ahydroxyaryl or hydroxyheteroaryl aldehyde III to furnish the aldehydeIV.

An alternative route to the amino acids IF is shown in Scheme 2. Thesecondary amino-ester VI is deprotected under standard conditions (basicconditions if the protecting group (PG) is methyl; acidic conditions ifPG is tert-butyl) to furnish the corresponding amino acid IE. Reductiveamination with an R^(3a) aldehyde under analogous conditions asdescribed in Scheme 1 furnishes the desired tertiary amino acid productsIF.

Alternatively, as shown in Scheme 3, the tertiary amino acids IF mayalso be obtained by alkylation of the secondary amino-ester VI with analkylating agent IX (with an appropriate leaving group (LG) such ashalide, mesylate, or tosylate) under standard conditions known in theart followed again by standard deprotection of the carboxylic acid esterX to provide the amino acids IF.

As shown in Scheme 4, the tertiary amino acid IF may also be assembledthrough reductive amination first of the R^(3a) aldehyde XI with anappropriate amine ester hydrochloride V. The resulting secondaryamine-ester XII then is subjected to reductive amination with theappropriate alkyl, aryl or heteroaryl aldehyde IV (as in Scheme 1)followed by deprotection of the carboxylic acid ester to give thedesired amino acid analogs IF.

For further substituted amino acids, a general synthetic scheme is shownin Scheme 5. Reductive amination of an appropriate amine XIII with anaryl or heteroaryl aldehyde XIV under standard conditions furnishes thecorresponding secondary amine XV, which is then reacted with ahalide-ester XVI (e.g. tert-butyl bromoacetate) to furnish thecorresponding α-amino ester XVII. This amine-ester XVII is thendeprotected under standard conditions to provide the desired amino acidanalogs IF.

The synthetic route in Scheme 5 also provides a general scheme for thesynthesis of the corresponding aminophosphonic acids IFA, as illustratedin Scheme 5a. The secondary amine XV is reacted with an appropriatelyprotected halide-phosphonate XVIA to provide the correspondingaminophosphonate ester XVIIA, which is then deprotected under standardconditions (Greene & Wuts) to furnish the amino phosphonic acid IFA.Scheme 5b illustrates the synthesis of the aminophosphinic acids IFB,which again involves the reaction of an appropriately protectedhalide-phosphinate ester XVIB with the secondary amine XV. Deprotectionof the resulting aminophosphinate ester then provides the phosphinicacid IFB.

An alternative to the sequence in Scheme 5 is shown in Scheme 6. Ahydroxyaryl or heteroaryl amine XVIII is selectively protected onnitrogen to provide protected amine XIX. A preferred R⁵(CH₂)_(n)OH (II)is then reacted with XIX under Mitsunobu conditions to provide thecorresponding ether, followed by deprotection of the amine, to form thefree amine XX. The free amine XX is then activated with a standardactivating group (2,4-dinitrobenzenesulfonamide; T. Fukuyama et al,Tetrahedron Lett. 1997, 38, 5831) and is then treated with an α-haloester XVI as in Scheme 5. The 2,4 dinitrobenzene-sulfonamide XXI isdeprotected under literature conditions (T. Fukuyama et al, TetrahedronLett., 1997, 38, 5831) to furnish a secondary α-amino-ester XXII whichis then subjected to a reductive amination with an R^(3a) aldehyde XIfollowed by deprotection of the ester X to furnish the desired analogsIF.

Scheme 7 describes an alternative general route to the amino acidanalogs IG. A hydroxyaryl or heteroaryl aldehyde III is subjected to theusual reductive amination conditions with an appropriate amine-esterhydrochloride V. The resulting secondary amine-ester XXIII isfunctionalized, in this case by a second reductive amination with anR^(3a) aldehyde VII to furnish the corresponding hydroxy tertiaryamine-ester XXIV. This can now undergo a Mitsunobu reaction with apreferred alcohol II (R⁵(CH₂)_(n)OH) which followed by deprotection ofthe ester XXV furnishes the desired analogs IG.

Scheme 8 describes a general synthesis of diaryl andaryl-heteroaryl-substituted amino acid analogs IH. The secondaryamine-ester XXII undergoes reductive amination with an appropriatelysubstituted formyl phenyl boronic acid XXVI under standard conditions togive the corresponding tertiary amine-ester boronic acid XXVII. The arylboronic acid XXVII can then undergo a Suzuki coupling (e.g. conditionsas described in Gibson, S. E., Transition Metals in Organic Synthesis, APractical Approach, pp. 47-50, 1997) with aryl or heteroaryl halidesXXVIII (especially bromides) to furnish the appropriate cross-couplingdiaryl products XXIX. Deprotection of the amine-ester XXIX generates thedesired amino acid analogs IH.

Scheme 9 describes a general synthesis of diaryl and aryl-heteroarylether-substituted amino acid analogs IJ. The tertiary amine-esterboronic acid XXVII which is described in Scheme 8 can be coupled withappropriately substituted phenols XXX under literature conditions (D. A.Evans et al, Tetrahedron Lett., 1998, 39, 2937) to furnish theappropriate diaryl or aryl-heteroaryl ethers XXXI, which afterdeprotection afford the desired amino acid analogs IJ.

Alternatively, as shown in Scheme 10, reductive amination of thesecondary amine-ester XXII with an appropriately substituted hydroxyarylor hydroxyheteroaryl aldehyde XXXII furnishes the correspondingphenol-tertiary amine-ester XXXIII. The phenol XXXIII can then undergocoupling with appropriate aryl or heteroaryl boronic acids XXXIV underliterature conditions (D. A. Evans et al, Tetrahedron Lett., 1998, 39,2937) to furnish the corresponding diaryl or arylheteroaryl ether-aminoesters XXXI. The desired analogs IJ are then obtained after deprotectionof the amine-ester XXXI.

Scheme 11 illustrates the synthesis of the carbamate-acid analogs IK.The secondary amine-ester XXII can be reacted with appropriatechloroformates XXXV under standard literature conditions (optimally inCH₂Cl₂ or CHCl₃ in the presence of a base such as Et₃N) to furnish thecorresponding carbamate-esters. The requisite analogs IK are thenobtained after deprotection of the carbamate-ester. Alternatively, thesecondary amine-ester XXII can be reacted with phosgene to generate thecorresponding carbamyl chloride XXXVI. This carbamyl chlorideintermediate XXXVI can be reacted with R^(3a)—OH (XXXVII)(optimallysubstituted phenols) to afford the corresponding carbamate-acids IKafter deprotection.

Scheme 12 illustrates the further functionalization of arylcarbamate-acid analogs IK. The secondary amine-ester XXII is reactedwith an aryl chloroformate XXXVIII (containing a protected hydroxylgroup) to form XXXIX. The hydroxyl group is then selectively deprotectedin the presence of the ester functionality to provide XL, then alkylatedwith an appropriate R⁶-LG (XLI) (where LG is halide, mesylate ortosylate, and R⁶ is most preferably CHF₂—, or CH₃CH₂—) in the presenceof base. Deprotection of the ester then furnishes the desiredcarbamate-acid analogs IL.

The secondary amine-ester XXIIA can be functionalized with substitutedaryl or aliphatic carboxylic acids XLII, under standard peptide couplingconditions, as illustrated in Scheme 13. The amide bond-formingreactions are conducted under standard peptide coupling procedures knownin the art. Optimally, the reaction is conducted in a solvent such asDMF at 0° C. to RT using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide(EDAC or EDCI or WSC), 1-hydroxybenzotriazole (HOBT) or1-hydroxy-7-azabenzotriazole (HOAT) and a base, for example Hunig's base(diisopropylethylamine), N-methyl morpholine or triethylamine.Deprotection of the amide-ester then furnishes the desired amide-acidanalogs IM.

The secondary amine-ester XXIIA can also be reacted with aliphatic oraryl isocyanates XLIII to provide the corresponding urea-esters.Deprotection of the urea-ester provides the desired urea-acid analogsIN, as shown in Scheme 14. Alternatively, as shown in Scheme 15, thecarbamyl chloride intermediate XXXVI described in Scheme 11 can bereacted with appropriate aliphatic or aryl amines XLIV in the presenceof a tertiary amine (e.g. Et₃N) to furnish tri- or tetrasubstitutedurea-acid analogs IO or IP after deprotection of the ester.

The secondary amine-ester XXIIA can also be reacted with appropriatesulfonyl chlorides XLVI under standard literature conditions (optimallyin the presence of a base such as pyridine, either neat or usingchloroform as a co-solvent), followed by deprotection, to provide thecorresponding sulfonamide-acids IQ, as shown in Scheme 16.

Replacement of the carboxylic acid functionality in these analogs withtetrazole can be achieved as shown in Scheme 17. An acid analog IK iscoupled with an amine (containing an appropriate tetrazole protectinggroup) XLVII (preferably 3-amino propionitrile) under standard peptidecoupling conditions. The resulting secondary amide XLVIII is thensubjected to a Mitsunobu reaction under standard conditions withtrimethylsilyl azide (TMSN₃) to form the protected tetrazole XLIX.Deprotection of the cyanoethyl group is achieved preferentially in thepresence of base to generate the desired free tetrazole analog IR.

Scheme 18 describes a general synthesis of the hydrazide-acid analogsIS. A substituted aryl carboxylic acid 1 is treated with methanesulfonylchloride in the presence of base; the intermediate is then reacted witha protected hydrazine-ester VA to give the corresponding acylatedhydrazine 1a (ref: Synthesis, 1989, 745-747). The acylhydrazine 1a iscoupled with an appropriately substituted aryl aldehyde IV underreductive amination conditions to give the corresponding protectedhydrazide ester 3 (ref: Can. J. Chem., 1998, 76, 1180-1187).Deprotection of the ester 3 then furnishes the hydrazide-acid analogsIS.

An alternative synthetic approach to hydrazide-acids IS is shown inScheme 19. An aryl aldehyde IV can be reduced to the correspondingalcohol under standard conditions (e.g NaBH₄). This alcohol is thenconverted to the corresponding bromide 4 using standard conditions (e.g.Ph₃P/CBr₄ or PBr₃). The bromide 4 is then reacted with thehydrazine-ester 1a (ref: Tetrahedron Lett., 1993, 34, 207-210) tofurnish the protected hydrazide-ester 3, which is then deprotected togive the hydrazide-acid analogs IS.

The different approaches to the preparation of the α-alkylbenzyl aminoacid and carbamate-acid analogs IT and IU are exemplified in thefollowing synthetic schemes. In Scheme 20 an appropriately substitutedaryl aldehyde IV is treated with a suitable organometallic reagent (e.g.a Grignard reagent R¹⁰MgBr) under standard conditions to give thecorresponding secondary alcohol, which is then oxidized under standardconditions (e.g. Swern oxidation with (COCl)₂/DMSO/Et₃N or usingpyridinium chlorochromate) to give the corresponding ketone 5. Reductiveamination of the ketone 5 with an appropriately substituted amino-ester6 provides the corresponding α-alkylbenzyl amino-ester 7. It will beunderstood that in the amino ester 6, the moiety

does not necessarily represent two repeating units.

Acylation of amino-ester 7 with an appropriately substituted aryl orheteroaryl chloroformate XXXV followed by deprotection provides theracemic carbamate-acid analogs IT. Reductive amination of alkylbenzylamino-ester 7 with aryl aldehyde VII followed by deprotection providesthe racemic amino-acid analogs IU.

Alternatively, as shown in Scheme 21, asymmetric reduction (e.g. usingthe Corey oxazaborolidine reduction protocol; review: E. J. Corey & C.Helal, Angew. Chem. Int. Ed. Engl., 1998, 37, 1986-2012.) of thearyl-ketone 5 provides each of the desired enantiomeric alcohols 8(although only one enantiomer is represented in the scheme). Treatmentof the chiral alcohol 8 with azide in a Mitsunobu-like reaction (ref: A.S. Thompson et. al., J. Org. Chem. 1993, 58, 5886-5888) gives thecorresponding chiral azide (with inverted stereochemistry from thestarting alcohol). The azide is then converted to the amine 9 bystandard reduction methods (e.g. hydrogenation or Ph₃P/THF/H₂O).Treatment of the chiral amine 9 with an ester XVIA (containing anappropriate leaving group) provides the secondary amino-ester 10.Acylation of amino-ester 10 with an aryl or heteroaryl chloroformateXXXV followed by deprotection provides the chiral carbamate-acid analogsITa (which may be either enantiomer depending upon the stereochemistryof 8). Reductive amination of alkyl amino-ester 10 with aryl aldehydesVII followed by deprotection provides the chiral amino-acid analogs IUa(which may be either enantiomer depending upon the stereochemistry of8).

An alternative to Scheme 21 is shown in Scheme 22. An appropriatelyprotected oxyaryl ketone 11 undergoes asymmetric reduction to give thechiral alcohol 12. This is converted to the chiral amine 13 via theidentical sequence as in Scheme 21 (via the chiral azide). Treatment ofthe chiral amine 13 with an ester XVIA (LG=halogen or mesylate) givesthe corresponding secondary amino-ester 14. Acylation of 14 with an arylor heteroaryl chloroformate XXXV provides the correspondingcarbamate-ester. Selective deprotection furnishes the free phenolcarbamate-ester 15. Alkylation of the phenol with a halide or mesylateVIII followed by deprotection provides the carbamate-acid analogs ITa.An analogous sequence (involving reductive amination of the secondaryamino-ester 14 with an aryl or heteroaryl aldehyde VII, then selectivedeprotection, alkylation with VIII and a final deprotection) providesthe amino acid analogs IUa.

It will be appreciated that either the (R)- or (S)-enantiomer of ITa orIUa may be synthesized in Schemes 21 and 22, depending upon thechirality of the reducing agent employed.

A fourth synthetic sequence is shown in Scheme 23. The substitutedaldehyde IV is condensed with an amino-ester hydrochloride 6 to give thecorresponding imine 16, which is then treated in situ with anappropriately substituted allylic halide 17 in the presence of indiummetal (reference: Loh, T.-P., et al., Tetrahedron Lett., 1997, 38,865-868) to give the α-allyl benzyl amino-ester 18. Acylation of amine18 with an aryl or heteroaryl chloroformate XXXV followed bydeprotection provides the carbamate-acid analogs Iv. Reductive aminationof alkyl amino-ester 18 with an aryl or heteroaryl aldehyde VII followedby deprotection provides the amino-acid analogs IW.

Scheme 24 shows the preparation of the required intermediate2-aryl-5-methyl-oxazol-4-yl methyl chloride 21 (following the generalprocedure described in Malamas, M. S., et al, J. Med. Chem., 1996, 39,237-245). A substituted aryl aldehyde 19 is condensed withbutane-2,3-dione mono-oxime under acidic conditions to give thecorresponding oxazole N-oxide 20. Deoxygenation of the oxazole N-oxide20 with concomitant chlorination furnishes the desired chloromethylaryl-oxazoles 21. Hydrolysis of chloromethyl oxazole 21 under basicconditions furnishes the corresponding oxazole-methanol 22. Oxidation ofalcohol 22 to the corresponding aldehyde is followed by conversion tothe corresponding dibromoalkene 23 (e.g. Ph₃P/CBr₄). The dibromide 23 isconverted to the corresponding alkynyl-lithium species (using anorganolithium reagent such as n-BuLi), which can be reacted in situ withan appropriate electrophile such as formaldehyde to give thecorresponding acetylenic alcohol (ref: Corey, E. J., et al., TetrahedronLett. 1972, 3769, or Gangakhedkar, K. K., Synth. Commun. 1996, 26,1887-1896). This alcohol can then be converted to the correspondingmesylate 24 and alkylated with an appropriate phenol 25 to provideanalogs Ix. Further stereoselective reduction (e.g. H₂/Lindlar'scatalyst) provides the E- or Z-alkenyl analogs IY.

Scheme 25 describes a general synthesis of the amino-benzoxazole analogsIZ (general ref: Sato, Y., et al, J. Med. Chem. 1998, 41, 3015-3021). Anappropriately substituted ortho-aminophenol 26 is treated with CS₂ inthe presence of base to furnish the corresponding mercapto-benzoxazole27. Treatment of this thiol 27 with an appropriate chlorinating agent(e.g. PCl₅) provides the key intermediate chlorobenzoxazole 28, which isreacted with the secondary amino-ester VI to furnish, afterdeprotection, the amino benzoxazole-acid analogs IZ.

The thiazole analogs IZa were synthesized according to the generalsynthetic route outlined in Scheme 26 (ref. Collins, J. L., et al., J.Med. Chem. 1998, 41, 5037). The secondary amino-ester XXIII is reactedwith an aryl or heteroaryl chloroformate XXXV in the presence of anappropriate base (e.g. pyridine or triethylamine) to furnish thecorresponding hydroxyaryl carbamate-ester 29. The hydroxyaryl ester 29is then reacted with an appropriately substituted α-bromo vinyl ketone29a (for S₁═CH₃, e.g. Weyerstahl, P., et. al., Flavour Fragr. J., 1998,13, 177 or Sokolov, N. A., et al., Zh. Org. Khim., 1980, 16, 281-283) inthe presence of an appropriate base (e.g. K₂CO₃) to give thecorresponding Michael reaction adduct, the α-bromoketone carbamate-ester30. The α-bromoketone 30 is then subjected to a condensation reactionwith an appropriately substituted aryl amide 31 (A=O) or aryl thioamide31 (A=S) to furnish either the corresponding oxazole (from the amide) orthe thiazole (from the thioamide) (ref: Malamas, M. S., et al, J. Med.Chem., 1996, 39, 237-245). Finally, deprotection of esters 31 thenprovides the substituted oxazole and thiazole carbamate acid analogsIZa.

It will be appreciated that in the following schemes where thecarbamate-acid analogs are prepared, the corresponding amino acidanalogs may also be prepared by replacing the chloroformate reactionwith an aldehyde in a reductive amination reaction (as in Scheme 20 withintermediate amine 7).

Scheme 27 describes a general synthesis of the acids IZb and IZc. Ahalo-substituted aryl aldehyde 32 (preferably iodide or bromide) issubjected to reductive amination using procedures known in theliterature (e.g. Abdel-Magid et al, J. Org. Chem. 1996, 61, 3849) withan α-amino acid ester hydrochloride V. The resulting secondaryamino-ester 33 is then reacted with an aryl or heteroaryl chloroformateXXXV in the presence of an appropriate base (e.g. pyridine ortriethylamine) to furnish the corresponding halo-aryl carbamate-ester34. Aryl halide 34 is then reacted with an appropriate aryl- orheteroaryl-substituted acetylene 35 (the preferred acetylene being5-phenyl-2-methyl-oxazol-4-yl-methylacetylene) in the presence of anappropriate palladium catalyst (e.g. (Ph₃P)₂PdCl₂) and a copper (I) salt(e.g. CuI) in a Sonogashira coupling reaction (ref: OrganocopperReagents, a Practical Approach, R. J. K. Taylor, Ed., Chapter 10, pp217-236, Campbell, I. B., Oxford University Press, 1994) to furnish thekey intermediate, arylacetylene carbamate ester 36.

The arylacetylene ester 36 is deprotected to provide the correspondingarylacetylene acid analogs IZb. The acetylene moiety of 36 can bereduced by standard methods (e.g. hydrogenation, ref: M. Hudlicky,Reductions in Organic Chemistry, 2^(nd) Edition, ACS, 1996, Chapter 1)to furnish the corresponding fully saturated alkyl aryl carbamate ester,which is then deprotected to give the alkyl aryl carbamate acid analogsIZc.

Stereoselective reduction of the acetylene ester 36 by standard methods(e.g. Lindlar's catalyst; ref: Preparation of Alkenes, A PracticalApproach, J. J. Williams, Ed., Chapter 6, pp 117-136, Oxford UniversityPress, 1996) can be achieved to provide the corresponding cis-alkenylaryl carbamate-ester, which is then deprotected to furnish the Z-alkenylaryl carbamate acid analogs IZd (Scheme 28). Alternatively, thissequence can be reversed, i.e. the initial step being the deprotectionof acetylenic ester 36 to the acetylenic acid, followed bystereoselective reduction of the acetylene moiety to provide theZ-alkene-acid analogs IZd.

The corresponding trans-alkenyl aryl carbamate acids IZe can besynthesized according to the general route in Scheme 29. An aryl- orheteroaryl-acetylene 35 (the preferred moiety again being5-phenyl-2-methyl-oxazol-4-yl-methylacetylene) is halogenated understandard conditions (ref: Boden, C. D. J. et al., J. Chem. Soc. PerkinTrans. I, 1996, 2417; or Lu, W. et. al., Tetrahedron Lett. 1998, 39,9521) to give the corresponding halo-acetylene, which is then convertedto the corresponding trans-alkenyl stannane 37 (ref: Boden, C. D. J., J.Chem. Soc., Perkin Trans. I, 1996, 2417). This aryl- orheteroaryl-substituted trans-alkenyl stannane 37 is then coupled withthe halo-aryl carbamate ester 34 under standard Stille couplingconditions (ref: Farina, V. et. al., “The Stille Reaction”, OrganicReactions, 1997, 50, 1) to furnish the corresponding trans-alkenyl arylcarbamate ester 38. This carbamate-ester is then deprotected understandard conditions to give the desired trans-alkenyl aryl carbamateacid analogs IZe.

The corresponding cyclopropyl analogs IZf and IZg are synthesizedaccording to Scheme 30. For the cis- or (Z-) cyclopropyl analogs,stereoselective reduction (H₂/Lindlar's catalyst) of the alkynyl moietyof intermediate alknyl ester 36 (as for analogs IZd), followed bycyclopropanation under standard conditions (Zhao, Y., et al, J. Org.Chem. 1995, 60, 5236-5242) and finally deprotection provides thecis-cyclopropyl carbamate-acid analogs IZf. For the trans-cyclopropylanalogs IF, analogous cyclopropanation of the E-alkene moiety ofintermediate 38 followed by deprotection provides the trans-cyclopropylcarbamate-acid analogs IZg.

A preferred alternative asymmetric synthesis of ITa (Scheme 21) is shownin Scheme 31. Protection of a chiral amine 39 (with the phenolprotected), preferably as a carbamate, provides intermediate 40. Removalof the phenolic protecting group of 40 provides the free phenol 41.Alkylation of phenol 41 with the mesylate VIII furnishes the protectedamine 42. Deprotection of this amine then furnishes the key intermediatesecondary amino-ester 9, which is then carried on to analogs ITa and IUaaccording to Scheme 21.

A preferred asymmetric synthesis of analogs IIA is shown in Scheme 32.The aldehyde IV is subjected to standard Wittig reaction conditions(ref: Preparation of Alkenes, a Practical Approach, J. J. Williams, Ed.,Chapter 2, pp 19-58) to furnish the alkene 43. Asymmetricaminohydroxylation according to known literature procedures (ref:O'Brien, P., Angew. Chem. Int. Ed., 1999, 38, 326 and Reddy, K. L., andSharpless, K. B., J. Am. Chem. Soc., 1998, 120, 1207) furnishes thedesired amino-alcohol 44 as a single enantiomer. Selective protection ofthe amine provides the alcohol 45. Alcohol 45 is then converted to theintermediate 46, which contains a suitable leaving group (either ahalide or a mesylate) for the subsequent cuprate reaction. Reaction ofan appropriate higher-order cuprate (ref: L. A. Paquette, Ed., OrganicReactions, 1992, Vol. 41, J. Wiley & Sons) with the protected aminesubstrate 46 provides the coupled protected amine 47. Deprotection ofthe amine functionality of 47, followed by reaction with an ester XVIA(LG=halogen or mesylate), furnishes the corresponding secondaryamino-ester 48. Acylation of 48 with an aryl or heteroaryl chloroformateXXXV provides the corresponding carbamate-ester, which is thendeprotected to furnish the carbamate-acid analogs IIA.

In this and the following Reaction Schemes:

Alternative Scheme 1A for Preparing Aldehyde IV

Unless otherwise indicated, the term “lower alkyl”, “alkyl” or “alk” asemployed herein alone or as part of another group includes both straightand branched chain hydrocarbons, containing 1 to 20 carbons, preferably1 to 10 carbons, more preferably 1 to 8 carbons, in the normal chain,and may optionally include an oxygen or nitrogen in the normal chain,such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl,pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the variousbranched chain isomers thereof, and the like as well as such groupsincluding 1 to 4 substituents such as halo, for example F, Br, Cl or Ior CF₃, alkoxy, aryl, aryloxy, aryl(aryl) or diaryl, arylalkyl,arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy,amino, hydroxy, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy,cycloheteroalkyl, arylheteroaryl, arylalkoxycarbonyl, heteroarylalkyl,heteroarylalkoxy, aryloxyalkyl, aryloxyaryl, alkylamido, alkanoylamino,arylcarbonylamino, nitro, cyano, thiol, haloalkyl, trihaloalkyl and/oralkylthio and/or any of the R³ groups.

Unless otherwise indicated, the term “cycloalkyl” as employed hereinalone or as part of another group includes saturated or partiallyunsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groupscontaining 1 to 3 rings, including monocyclicalkyl, bicyclicalkyl andtricyclicalkyl, containing a total of 3 to 20 carbons forming the rings,preferably 3 to 10 carbons, forming the ring and which may be fused to 1or 2 aromatic rings as described for aryl, which include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyland cyclododecyl, cyclohexenyl,

any of which groups may be optionally substituted with 1 to 4substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy,arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl,arylcarbonylamino, amino, nitro, cyano, thiol and/or alkylthio and/orany of the substituents for alkyl.

The term “cycloalkenyl” as employed herein alone or as part of anothergroup refers to cyclic hydrocarbons containing 3 to 12 carbons,preferably 5 to 10 carbons and 1 or 2 double bonds. Exemplarycycloalkenyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl,cyclooctenyl, cyclohexadienyl, and cycloheptadienyl, which may beoptionally substituted as defined for cycloalkyl.

The term “cycloalkylene” as employed herein refers to a “cycloalkyl”group which includes free bonds and thus is a linking group such as

and the like, and may optionally be substituted as defined above for“cycloalkyl”.

The term “alkanoyl” as used herein alone or as part of another grouprefers to alkyl linked to a carbonyl group.

Unless otherwise indicated, the term “lower alkenyl” or “alkenyl” asused herein by itself or as part of another group refers to straight orbranched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbons,and more preferably 1 to 8 carbons in the normal chain, which includeone to six double bonds in the normal chain, and may optionally includean oxygen or nitrogen in the normal chain, such as vinyl, 2-propenyl,3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl,2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl,3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, and the like, andwhich may be optionally substituted with 1 to 4 substituents, namely,halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl,cycloalkyl, amino, hydroxy, heteroaryl, cycloheteroalkyl, alkanoylamino,alkylamido, arylcarbonylamino, nitro, cyano, thiol, alkylthio and/or anyof the substituents for alkyl set out herein.

Unless otherwise indicated, the term “lower alkynyl” or “alkynyl” asused herein by itself or as part of another group refers to straight orbranched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbonsand more preferably 2 to 8 carbons in the normal chain, which includeone triple bond in the normal chain, and may optionally include anoxygen or nitrogen in the normal chain, such as 2-propynyl, 3-butynyl,2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl,3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl,3-undecynyl,4-dodecynyl and the like, and which may be optionally substituted with 1to 4 substituents, namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl,alkynyl, aryl, arylalkyl, cycloalkyl, amino, heteroaryl,cycloheteroalkyl, hydroxy, alkanoylamino, alkylamido, arylcarbonylamino,nitro, cyano, thiol, and/or alkylthio, and/or any of the substituentsfor alkyl set out herein.

The terms “arylalkenyl” and “arylalkynyl” as used alone or as part ofanother group refer to alkenyl and alkynyl groups as described abovehaving an aryl substituent.

Where alkyl groups as defined above have single bonds for attachment toother groups at two different carbon atoms, they are termed “alkylene”groups and may optionally be substituted as defined above for “alkyl”.

Where alkenyl groups as defined above and alkynyl groups as definedabove, respectively, have single bonds for attachment at two differentcarbon atoms, they are termed “alkenylene groups” and “alkynylenegroups”, respectively, and may optionally be substituted as definedabove for “alkenyl” and “alkynyl”.

X¹ _(x), X¹ _(m) and X¹ _(n) which may also be referred to as (CH₂)_(x),(CH₂)_(m), and (CH₂)_(n), respectively, or (CH₂)_(y) includes alkylene,allenyl, alkenylene or alkynylene groups, as defined herein, each ofwhich may optionally include an oxygen or nitrogen in the normal chain,which may optionally include 1, 2, or 3 substituents which includealkyl, alkenyl, halogen, cyano, hydroxy, alkoxy, amino, thioalkyl, keto,C₃-C₆ cycloalkyl, alkylcarbonylamino or alkylcarbonyloxy; the alkylsubstituent may be an alkylene moiety of 1 to 4 carbons which may beattached to one or two carbons in the (CH₂)_(x) or (CH₂)_(m) or(CH₂)_(n) group to form a cycloalkyl group therewith.

Examples of (CH₂)_(x), (CH₂) m, (CH₂)_(n), (CH₂) y, alkylene, alkenyleneand alkynylene include

The term “halogen” or “halo” as used herein alone or as part of anothergroup refers to chlorine, bromine, fluorine, and iodine as well as CF₃,with chlorine or fluorine being preferred.

The term “metal ion” refers to alkali metal ions such as sodium,potassium or lithium and alkaline earth metal ions such as magnesium andcalcium, as well as zinc and aluminum.

Unless otherwise indicated, the term “aryl” or the group

where Q is C, as employed herein alone or as part of another grouprefers to monocyclic and bicyclic aromatic groups containing 6 to 10carbons in the ring portion (such as phenyl or naphthyl including1-naphthyl and 2-naphthyl) and may optionally include one to threeadditional rings fused to a carbocyclic ring or a heterocyclic ring(such as aryl, cycloalkyl, heteroaryl or cycloheteroalkyl rings forexample

and may be optionally substituted through available carbon atoms with 1,2, or 3 groups selected from hydrogen, halo, haloalkyl, alkyl,haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl,trifluoromethoxy, alkynyl, cycloalkyl-alkyl, cycloheteroalkyl,cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy,aryloxyalkyl, arylalkoxy, alkoxycarbonyl, arylcarbonyl, arylalkenyl,aminocarbonylaryl, arylthio, arylsulfinyl, arylazo, heteroarylalkyl,heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro,cyano, amino, substituted amino wherein the amino includes 1 or 2substituents (which are alkyl, aryl or any of the other aryl compoundsmentioned in the definitions), thiol, alkylthio, arylthio,heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl,arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl,aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino,arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino orarylsulfonaminocarbonyl and/or any of the substituents for alkyl set outherein.

Unless otherwise indicated, the term “lower alkoxyy”, “alkoxy”,“aryloxy” or “aralkoxy” as employed herein alone or as part of anothergroup includes any of the above alkyl, aralkyl or aryl groups linked toan oxygen atom.

Unless otherwise indicated, the term “substituted amino” as employedherein alone or as part of another group refers to amino substitutedwith one or two substituents, which may be the same or different, suchas alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl,haloalkyl, hydroxyalkyl, alkoxyalkyl or thioalkyl. These substituentsmay be further substituted with a carboxylic acid and/or any of thesubstituents for alkyl as set out above. In addition, the aminosubstituents may be taken together with the nitrogen atom to which theyare attached to form 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl,4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl,4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl, 1-pyrrolidinyl,1-piperidinyl, or 1-azepinyl, optionally substituted with alkyl, alkoxy,alkylthio, halo, trifluoromethyl or hydroxy.

Unless otherwise indicated, the term “lower alkylthio”, “alkylthio”,“arylthio” or “aralkylthio” as employed herein alone or as part ofanother group includes any of the above alkyl, aralkyl or aryl groupslinked to a sulfur atom.

Unless otherwise indicated, the term “lower alkylamino”, “alkylamino”,“arylamino”, or “arylalkylamino” as employed herein alone or as part ofanother group includes any of the above alkyl, aryl or arylalkyl groupslinked to a nitrogen atom.

Unless otherwise indicated, the term “acyl” as employed herein by itselfor part of another group, as defined herein, refers to an organicradical linked to a carbonyl

group; examples of acyl groups include any of the R³ groups attached toa carbonyl, such as alkanoyl, alkenoyl, aroyl, aralkanoyl, heteroaroyl,cycloalkanoyl, cycloheteroalkanoyl and the like.

Unless otherwise indicated, the term “cycloheteroalkyl” as used hereinalone or as part of another group refers to a 5-, 6- or 7-memberedsaturated or partially unsaturated ring which includes 1 to 2 heteroatoms such as nitrogen, oxygen and/or sulfur, linked through a carbonatom or a heteroatom, where possible, optionally via the linker(CH₂)_(p) (where p is 1, 2 or 3), such as

and the like. The above groups may include 1 to 4 substituents such asalkyl, halo, oxo and/or any of of the substituents for alkyl or aryl setout herein. In addition, any of the cycloheteroalkyl rings can be fusedto a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring.

Unless otherwise indicated, the term “heteroaryl” as used herein aloneor as part of another group refers to a 5- or 6-membered aromatic ringincluding

where Q is N, which includes 1, 2, 3 or 4 hetero atoms such as nitrogen,oxygen or sulfur, and such rings fused to an aryl, cycloalkyl,heteroaryl or cycloheteroalkyl ring (e.g. benzothiophenyl, indolyl), andincludes possible N-oxides. The heteroaryl group may optionally include1 to 4 substituents such as any of the substituents for alkyl or arylset out above. Examples of heteroaryl groups include the following:

and the like.

The term “cycloheteroalkylalkyl” as used herein alone or as part ofanother group refers to cycloheteroalkyl groups as defined above linkedthrough a C atom or heteroatom to a (CH₂)_(p) chain.

The term “heteroarylalkyl” or “heteroarylalkenyl” as used herein aloneor as part of another group refers to a heteroaryl group as definedabove linked through a C atom or heteroatom to a —(CH₂)_(p)— chain,alkylene or alkenylene as defined above.

The term “polyhaloalkyl” as used herein refers to an “alkyl” group asdefined above which includes from 2 to 9, preferably from 2 to 5, halosubstituents, such as F or Cl, preferably F, such as CF₃CH₂, CF₃ orCF₃CF₂CH₂.

The term “polyhaloalkyloxy” as used herein refers to an “alkoxy” or“alkyloxy” group as defined above which includes from 2 to 9, preferablyfrom 2 to 5, halo substituents, such as F or Cl, preferably F, such asCF₃CH₂O, CF₃O or CF₃CF₂CH₂O.

The term “prodrug esters” as employed herein includes prodrug esterswhich are known in the art for carboxylic and phosphorus acid esterssuch as methyl, ethyl, benzyl and the like. Other prodrug ester examplesof R⁴ include the following groups:

(1-alkanoyloxy)alkyl such as,

wherein R^(a), R^(b) and R^(c) are H, alkyl, aryl or arylalkyl; however,R^(a)O cannot be HO.Examples of such prodrug esters R⁴ include

Other examples of suitable prodrug esters R⁴ include

wherein R^(a) can be H, alkyl (such as methyl or t-butyl), arylalkyl(such as benzyl) or aryl (such as phenyl); R^(d) is H, alkyl, halogen oralkoxy, R^(e) is alkyl, aryl, arylalkyl or alkoxyl, and n₁ is 0, 1 or 2.

Where the compounds of structure I are in acid form they may form apharmaceutically acceptable salt such as alkali metal salts such aslithium, sodium or potassium, alkaline earth metal salts such as calciumor magnesium as well as zinc or aluminum and other cations such asammonium, choline, diethanolamine, lysine (D or L), ethylenediamine,t-butylamine, t-octylamine, tris-(hydroxymethyl)aminomethane (TRIS),N-methyl glucosamine (NMG), triethanolamine and dehydroabietylamine.

All stereoisomers of the compounds of the instant invention arecontemplated, either in admixture or in pure or substantially pure form.The compounds of the present invention can have asymmetric centers atany of the carbon atoms including any one or the R substituents.Consequently, compounds of formula I can exist in enantiomeric ordiastereomeric forms or in mixtures thereof. The processes forpreparation can utilize racemates, enantiomers or diastereomers asstarting materials. When diastereomeric or enantiomeric products areprepared, they can be separated by conventional methods for example,chromatographic or fractional crystallization.

Where desired, the compounds of structure I may be used in combinationwith one or more hypolipidemic agents or lipid-lowering agents and/orone or more other types of therapeutic agents including antidiabeticagents, anti-obesity agents, antihypertensive agents, plateletaggregation inhibitors, and/or anti-osteoporosis agents, which may beadministered orally in the same dosage form, in a separate oral dosageform or by injection.

The hypolipidemic agent or lipid-lowering agent which may be optionallyemployed in combination with the compounds of formula I of the inventionmay include 1,2,3 or more MTP inhibitors, HMG CoA reductase inhibitors,squalene synthetase inhibitors, fibric acid derivatives, ACATinhibitors, lipoxygenase inhibitors, cholesterol absorption inhibitors,ileal Na⁺/bile acid cotransporter inhibitors, upregulators of LDLreceptor activity, bile acid sequestrants, and/or nicotinic acid andderivatives thereof.

MTP inhibitors employed herein include MTP inhibitors disclosed in U.S.Pat. No. 5,595,872, U.S. Pat. No. 5,739,135, U.S. Pat. No. 5,712,279,U.S. Pat. No. 5,760,246, U.S. Pat. No. 5,827,875, U.S. Pat. No.5,885,983 and U.S. application Ser. No. 09/175,180 filed Oct. 20, 1998,now U.S. Pat. No. 5,962,440. Preferred are each of the preferred MTPinhibitors disclosed in each of the above patents and applications.

All of the above U.S. patents and applications are incorporated hereinby reference.

Most preferred MTP inhibitors to be employed in accordance with thepresent invention include preferred MTP inhibitors as set out in U.S.Pat. Nos. 5,739,135 and 5,712,279, and U.S. Pat. No. 5,760,246.

The most preferred MTP inhibitor is9-[4-[4-[[2-(2,2,2-Trifluoroethoxy)benzoyl]amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide

The hypolipidemic agent may be an HMG CoA reductase inhibitor whichincludes, but is not limited to, mevastatin and related compounds asdisclosed in U.S. Pat. No. 3,983,140, lovastatin (mevinolin) and relatedcompounds as disclosed in U.S. Pat. No. 4,231,938, pravastatin andrelated compounds such as disclosed in U.S. Pat. No. 4,346,227,simvastatin and related compounds as disclosed in U.S. Pat. Nos.4,448,784 and 4,450,171. Other HMG CoA reductase inhibitors which may beemployed herein include, but are not limited to, fluvastatin, disclosedin U.S. Pat. No. 5,354,772, cerivastatin disclosed in U.S. Pat. Nos.5,006,530 and 5,177,080, atorvastatin disclosed in U.S. Pat. Nos.4,681,893, 5,273,995, 5,385,929 and 5,686,104, itavastatin(Nissan/Sankyo's nisvastatin (NK-104)) disclosed in U.S. Pat. No.5,011,930, Shionogi-Astra/Zeneca visastatin (ZD-4522) disclosed in U.S.Pat. No. 5,260,440, and related statin compounds disclosed in U.S. Pat.No. 5,753,675, pyrazole analogs of mevalonolactone derivatives asdisclosed in U.S. Pat. No. 4,613,610, indene analogs of mevalonolactonederivatives as disclosed in PCT application WO 86/03488,6-[2-(substituted-pyrrol-1-yl)-alkyl)pyran-2-ones and derivativesthereof as disclosed in U.S. Pat. No. 4,647,576, Searle's SC-45355 (a3-substituted pentanedioic acid derivative) dichloroacetate, imidazoleanalogs of mevalonolactone as disclosed in PCT application WO 86/07054,3-carboxy-2-hydroxy-propane-phosphonic acid derivatives as disclosed inFrench Patent No. 2,596,393, 2,3-disubstituted pyrrole, furan andthiophene derivatives as disclosed in European Patent Application No.0221025, naphthyl analogs of mevalonolactone as disclosed in U.S. Pat.No. 4,686,237, octahydronaphthalenes such as disclosed in U.S. Pat. No.4,499,289, keto analogs of mevinolin (lovastatin) as disclosed inEuropean Patent Application No. 0,142,146 A2, and quinoline and pyridinederivatives disclosed in U.S. Pat. Nos. 5,506,219 and 5,691,322.

In addition, phosphinic acid compounds useful in inhibiting HMG CoAreductase suitable for use herein are disclosed in GB 2205837.

The squalene synthetase inhibitors suitable for use herein include, butare not limited to, α-phosphono-sulfonates disclosed in U.S. Pat. No.5,712,396, those disclosed by Biller et al, J. Med. Chem., 1988, Vol.31, No. 10, pp 1869-1871, including isoprenoid(phosphinyl-methyl)phosphonates as well as other known squalenesynthetase inhibitors, for example, as disclosed in U.S. Pat. Nos.4,871,721 and 4,924,024 and in Biller, S. A., Neuenschwander, K.,Ponpipom, M. M., and Poulter, C. D., Current Pharmaceutical Design, 2,1-40 (1996).

In addition, other squalene synthetase inhibitors suitable for useherein include the terpenoid pyrophosphates disclosed by P. Ortiz deMontellano et al, J. Med. Chem., 1977, 20, 243-249, the farnesyldiphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs asdisclosed by Corey and Volante, J. Am. Chem. Soc., 1976, 98, 1291-1293,phosphinylphosphonates reported by McClard, R. W. et al, J.A.C.S., 1987,109, 5544 and cyclopropanes reported by Capson, T. L., PhD dissertation,June, 1987, Dept. Med. Chem. U of Utah, Abstract, Table of Contents, pp16, 17, 40-43, 48-51, Summary.

Other hypolipidemic agents suitable for use herein include, but are notlimited to, fibric acid derivatives, such as fenofibrate, gemfibrozil,clofibrate, bezafibrate, ciprofibrate, clinofibrate and the like,probucol, and related compounds as disclosed in U.S. Pat. No. 3,674,836,probucol and gemfibrozil being preferred, bile acid sequestrants such ascholestyramine, colestipol and DEAE-Sephadex (Secholex®, Policexide®)and cholestagel (Sankyo/Geltex), as well as lipostabil (Rhone-Poulenc),Eisai E-5050 (an N-substituted ethanolamine derivative), imanixil(HOE-402), tetrahydrolipstatin (THL), istigmastanylphos-phorylcholine(SPC, Roche), aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814(azulene derivative), melinamide (Sumitomo), Sandoz 58-035, AmericanCyanamid CL-277,082 and CL-283,546 (disubstituted urea derivatives),nicotinic acid (niacin), acipimox, acifran, neomycin, p-aminosalicylicacid, aspirin, poly(diallylmethylamine) derivatives such as disclosed inU.S. Pat. No. 4,759,923, quaternary amine poly(diallyldimethylammoniumchloride) and ionenes such as disclosed in U.S. Pat. No. 4,027,009, andother known serum cholesterol lowering agents.

The hypolipidemic agent may be an ACAT inhibitor such as disclosed in,Drugs of the Future 24, 9-15 (1999), (Avasimibe); “The ACAT inhibitor,Cl-1011 is effective in the prevention and regression of aortic fattystreak area in hamsters”, Nicolosi et al, Atherosclerosis (Shannon,Irel). (1998), 137(1), 77-85; “The pharmacological profile of FCE 27677:a novel ACAT inhibitor with potent hypolipidemic activity mediated byselective suppression of the hepatic secretion of ApoB100-containinglipoprotein”, Ghiselli, Giancarlo, Cardiovasc. Drug Rev. (1998), 16(1),16-30; “RP 73163: a bioavailable alkylsulfinyl-diphenylimidazole ACATinhibitor”, Smith, C., et al, Bioorg. Med. Chem. Lett. (1996), 6(1),47-50; “ACAT inhibitors: physiologic mechanisms for hypolipidemic andanti-atherosclerotic activities in experimental animals”, Krause et al,Editor(s): Ruffolo, Robert R., Jr.; Hollinger, Mannfred A.,Inflammation: Mediators Pathways (1995), 173-98, Publisher: CRC, BocaRaton, Fla.; “ACAT inhibitors: potential anti-atherosclerotic agents”,Sliskovic et al, Curr. Med. Chem. (1994), 1(3), 204-25; “Inhibitors ofacyl-CoA:cholesterol O-acyl transferase (ACAT) as hypocholesterolemicagents. 6. The first water-soluble ACAT inhibitor with lipid-regulatingactivity. Inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). 7.Development of a series of substitutedN-phenyl-N′-[(1-phenylcyclopentyl)methyl]ureas with enhancedhypocholesterolemic activity”, Stout et al, Chemtracts: Org. Chem.(1995), 8(6), 359-62, or TS-962 (Taisho Pharmaceutical Co. Ltd).

The hypolipidemic agent may be an upregulator of LD2 receptor activitysuch as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427 (Eli Lilly).

The hypolipidemic agent may be a cholesterol absorption inhibitorpreferably Schering-Plough's SCH48461 as well as those disclosed inAtherosclerosis 115, 45-63 (1995) and J. Med. Chem. 41, 973 (1998).

The hypolipidemic agent may be an ileal Na⁺/bile acid cotransporterinhibitor such as disclosed in Drugs of the Future, 24, 425-430 (1999).

The lipid-modulating agent may be a cholesteryl ester transfer protein(CETP) inhibitor such as Pfizer's CP 529,414 (WO/0038722 and EP 818448)and Pharmacia's SC-744 and SC-795.

The ATP citrate lyase inhibitor which may be employed in the combinationof the invention may include, for example, those disclosed in U.S. Pat.No. 5,447,954.

Preferred hypolipidemic agents are pravastatin, lovastatin, simvastatin,atorvastatin, fluvastatin, cerivastatin, itavastatin and visastatin andZD-4522.

The above-mentioned U.S. patents are incorporated herein by reference.The amounts and dosages employed will be as indicated in the Physician'sDesk Reference and/or in the patents set out above.

The compounds of formula I of the invention will be employed in a weightratio to the hypolipidemic agent (were present), within the range fromabout 500:1 to about 1:500, preferably from about 100:1 to about 1:100.

The dose administered must be carefully adjusted according to age,weight and condition of the patient, as well as the route ofadministration, dosage form and regimen and the desired result.

The dosages and formulations for the hypolipidemic agent will be asdisclosed in the various patents and applications discussed above.

The dosages and formulations for the other hypolipidemic agent to beemployed, where applicable, will be as set out in the latest edition ofthe Physicians' Desk Reference.

For oral administration, a satisfactory result may be obtained employingthe MTP inhibitor in an amount within the range of from about 0.01 mg toabout 500 mg and preferably from about 0.1 mg to about 100 mg, one tofour times daily.

A preferred oral dosage form, such as tablets or capsules, will containthe MTP inhibitor in an amount of from about 1 to about 500 mg,preferably from about 2 to about 400 mg, and more preferably from about5 to about 250 mg, one to four times daily.

For oral administration, a satisfactory result may be obtained employingan HMG CoA reductase inhibitor, for example, pravastatin, lovastatin,simvastatin, atorvastatin, fluvastatin or cerivastatin in dosagesemployed as indicated in the Physician's Desk Reference, such as in anamount within the range of from about 1 to 2000 mg, and preferably fromabout 4 to about 200 mg.

The squalene synthetase inhibitor may be employed in dosages in anamount within the range of from about 10 mg to about 2000 mg andpreferably from about 25 mg to about 200 mg.

A preferred oral dosage form, such as tablets or capsules, will containthe HMG CoA reductase inhibitor in an amount from about 0.1 to about 100mg, preferably from about 0.5 to about 80 mg, and more preferably fromabout 1 to about 40 mg.

A preferred oral dosage form, such as tablets or capsules will containthe squalene synthetase inhibitor in an amount of from about 10 to about500 mg, preferably from about 25 to about 200 mg.

The hypolipidemic agent may also be a lipoxygenase inhibitor including a15-lipoxygenase (15-LO) inhibitor such as benzimidazole derivatives asdisclosed in WO 97/12615, 15-LO inhibitors as disclosed in WO 97/12613,isothiazolones as disclosed in WO 96/38144, and 15-LO inhibitors asdisclosed by Sendobry et al “Attenuation of diet-induced atherosclerosisin rabbits with a highly selective 15-lipoxygenase inhibitor lackingsignificant antioxidant properties”, Brit. J. Pharmacology (1997) 120,1199-1206, and Cornicelli et al, “15-Lipoxygenase and its Inhibition: ANovel Therapeutic Target for Vascular Disease”, Current PharmaceuticalDesign, 1999, 5, 11-20.

The compounds of formula I and the hypolipidemic agent may be employedtogether in the same oral dosage form or in separate oral dosage formstaken at the same time.

The compositions described above may be administered in the dosage formsas described above in single or divided doses of one to four timesdaily. It may be advisable to start a patient on a low dose combinationand work up gradually to a high dose combination.

The preferred hypolipidemic agent is pravastatin, simvastatin,lovastatin, atorvastatin, fluvastatin or cerivastatin as well as niacinand/or cholestagel.

The other antidiabetic agent which may be optionally employed incombination with the compound of formula I may be 1, 2, 3 or moreantidiabetic agents or antihyperglycemic agents including insulinsecretagogues or insulin sensitizers, or other antidiabetic agentspreferably having a mechanism of action different from the compounds offormula I of the invention, which may include biguanides, sulfonylureas, glucosidase inhibitors, PPAR γ agonists, such asthiazolidinediones, aP2 inhibitors, dipeptidyl peptidase IV (DP4)inhibitors, SGLT2 inhibitors, and/or meglitinides, as well as insulin,and/or glucagon-like peptide-1 (GLP-1).

The other antidiabetic agent may be an oral antihyperglycemic agentpreferably a biguanide such as metformin or phenformin or salts thereof,preferably metformin HCl.

Where the antidiabetic agent is a biguanide, the compounds of structureI will be employed in a weight ratio to biguanide within the range fromabout 0.001:1 to about 10:1, preferably from about 0.01:1 to about 5:1.

The other antidiabetic agent may also preferably be a sulfonyl urea suchas glyburide (also known as glibenclamide), glimepiride (disclosed inU.S. Pat. No. 4,379,785), glipizide, gliclazide or chlorpropamide, otherknown sulfonylureas or other antihyperglycemic agents which act on theATP-dependent channel of the β-cells, with glyburide and glipizide beingpreferred, which may be administered in the same or in separate oraldosage forms.

The compounds of structure I will be employed in a weight ratio to thesulfonyl urea in the range from about 0.01:1 to about 100:1, preferablyfrom about 0.02:1 to about 5:1.

The oral antidiabetic agent may also be a glucosidase inhibitor such asacarbose (disclosed in U.S. Pat. No. 4,904,769) or miglitol (disclosedin U.S. Pat. No. 4,639,436), which may be administered in the same or ina separate oral dosage forms.

The compounds of structure I will be employed in a weight ratio to theglucosidase inhibitor within the range from about 0.01:1 to about 100:1,preferably from about 0.05:1 to about 10:1.

The compounds of structure I may be employed in combination with a PPARγ agonist such as a thiazolidinedione oral anti-diabetic agent or otherinsulin sensitizers (which has an insulin sensitivity effect in NIDDMpatients) such as troglitazone (Warner-Lambert's Rezulin®, disclosed inU.S. Pat. No. 4,572,912), rosiglitazone (SKB), pioglitazone (Takeda),Mitsubishi's MCC-555 (disclosed in U.S. Pat. No. 5,594,016),Glaxo-Welcome's GL-262570, englitazone (CP-68722, Pfizer) ordarglitazone (CP-86325, Pfizer, isaglitazone (MIT/J&J), JTT-501(JPNT/P&U), L-895645 (Merck), R-119702 (Sankyo/WL), NN-2344 (Dr.Reddy/NN), or YM-440 (Yamanouchi), preferably rosiglitazone andpioglitazone.

The compounds of structure I will be employed in a weight ratio to thethiazolidinedione in an amount within the range from about 0.01:1 toabout 100:1, preferably from about 0.05 to about 10:1.

The sulfonyl urea and thiazolidinedione in amounts of less than about150 mg oral antidiabetic agent may be incorporated in a single tabletwith the compounds of structure I.

The compounds of structure I may also be employed in combination with aantihyperglycemic agent such as insulin or with glucagon-like peptide-1(GLP-1) such as GLP-1 (1-36) amide, GLP-1 (7-36) amide, GLP-1 (7-37) (asdisclosed in U.S. Pat. No. 5,614,492 to Habener, the disclosure of whichis incorporated herein by reference), as well as AC2993 (Amylin) andLY-315902 (Lilly), which may be administered via injection, intranasal,inhalation or by transdermal or buccal devices.

Where present, metformin, the sulfonyl ureas, such as glyburide,glimepiride, glipyride, glipizide, chlorpropamide and gliclazide and theglucosidase inhibitors acarbose or miglitol or insulin (injectable,pulmonary, buccal, or oral) may be employed in formulations as describedabove and in amounts and dosing as indicated in the Physician's DeskReference (PDR).

Where present, metformin or salt thereof may be employed in amountswithin the range from about 500 to about 2000 mg per day which may beadministered in single or divided doses one to four times daily.

Where present, the thiazolidinedione anti-diabetic agent may be employedin amounts within the range from about 0.01 to about 2000 mg/day whichmay be administered in single or divided doses one to four times perday.

Where present insulin may be employed in formulations, amounts anddosing as indicated by the Physician's Desk Reference.

Where present GLP-1 peptides may be administered in oral buccalformulations, by nasal administration or parenterally as described inU.S. Pat. No. 5,346,701 (TheraTech), U.S. Pat. Nos. 5,614,492 and5,631,224 which are incorporated herein by reference.

The other antidiabetic agent may also be a PPAR α/γ dual agonist such asAR-HO39242 (Astra/Zeneca), GW-409544 (Glaxo-Wellcome), KRP297 (KyorinMerck) as well as those disclosed by Murakami et al, “A Novel InsulinSensitizer Acts As a Coligand for Peroxisome Proliferation—ActivatedReceptor Alpha (PPAR alpha) and PPAR gamma. Effect on PPAR alphaActivation on Abnormal Lipid Metabolism in Liver of Zucker Fatty Rats”,Diabetes 47, 1841-1847 (1998).

The antidiabetic agent may be an SGLT2 inhibitor such as disclosed inU.S. provisional application No. 60/158,773, filed Oct. 12, 1999(attorney file LA49), employing dosages as set out therein. Preferredare the compounds designated as preferred in the above application.

The antidiabetic agent may be an aP2 inhibitor such as disclosed in U.S.application Ser. No. 09/391,053, filed Sep. 7, 1999, and in U.S.provisional application No. 60/127,745, filed Apr. 5, 1999 (attorneyfile LA27*), employing dosages as set out herein. Preferred are thecompounds designated as preferred in the above application.

The antidiabetic agent may be a DP4 inhibitor such as disclosed inProvisional Application 60/188,555 filed Mar. 10, 2000 (attorney fileLA50), WO99/38501, WO99/46272, WO99/67279 (PROBIODRUG), WO99/67278(PROBIODRUG), WO99/61431 (PROBIODRUG), NVP-DPP728A(1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine)(Novartis) (preferred) as disclosed by Hughes et al, Biochemistry,38(36), 11597-11603, 1999, TSL-225(tryptophyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (disclosedby Yamada et al, Bioorg. & Med. Chem. Lett. 8 (1998) 1537-1540,2-cyanopyrrolidides and 4-cyanopyrrolidides as disclosed by Ashworth etal, Bioorg. & Med. Chem. Lett., Vol. 6, No. 22, pp 1163-1166 and2745-2748 (1996) employing dosages as set out in the above references.

The meglitinide which may optionally be employed in combination with thecompound of formula I of the invention may be repaglinide, nateglinide(Novartis) or KAD1229 (PF/Kissei), with repaglinide being preferred.

The compound of formula I will be employed in a weight ratio to themeglitinide, PPAR γ agonist, PPAR α/γ dual agonist, aP2 inhibitor, DP4inhibitor or SGLT2 inhibitor within the range from about 0.01:1 to about100:1, preferably from about 0.05 to about 10:1.

The other type of therapeutic agent which may be optionally employedwith a compound of formula I may be 1, 2, 3 or more of an anti-obesityagent including a beta 3 adrenergic agonist, a lipase inhibitor, aserotonin (and dopamine) reuptake inhibitor, an aP2 inhibitor, a thyroidreceptor agonist and/or an anorectic agent.

The beta 3 adrenergic agonist which may be optionally employed incombination with a compound of formula I may be AJ9677(Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) or other knownbeta 3 agonists as disclosed in U.S. Pat. Nos. 5,541,204, 5,770,615,5,491,134, 5,776,983 and 5,488,064, with AJ9677, L750,355 and CP331648being preferred.

The lipase inhibitor which may be optionally employed in combinationwith a compound of formula I may be orlistat or ATL-962 (Alizyme), withorlistat being preferred.

The serotonin (and dopoamine) reuptake inhibitor which may be optionallyemployed in combination with a compound of formula I may be sibutramine,topiramate (Johnson & Johnson) or axokine (Regeneron), with sibutramineand topiramate being preferred.

The thyroid receptor agonist which may be optionally employed incombination with a compound of formula I may be a thyroid receptorligand as disclosed in WO97/21993 (U. Cal SF), WO99/00353 (KaroBio),GB98/284425 (KaroBio), and U.S. Provisional Application 60/183,223 filedFeb. 17, 2000, with compounds of the KaroBio applications and the aboveU.S. provisional application being preferred.

The anorectic agent which may be optionally employed in combination witha compound of formula I may be dexamphetamine, phentermine,phenylpropanolamine or mazindol, with dexamphetamine being preferred.

The various anti-obesity agents described above may be employed in thesame dosage form with the compound of formula I or in different dosageforms, in dosages and regimens as generally known in the art or in thePDR.

The antihypertensive agents which may be employed in combination withthe compound of formula I of the invention include ACE inhibitors,angiotensin II receptor antagonists, NEP/ACE inhibitors, as well ascalcium channel blockers, β-adrenergic blockers and other types ofantihypertensive agents including diuretics.

The angiotensin converting enzyme inhibitor which may be employed hereinincludes those containing a mercapto (—S—) moiety such as substitutedproline derivatives, such as any of those disclosed in U.S. Pat. No.4,046,889 to Ondetti et al mentioned above, with captopril, that is,1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline, being preferred, andmercaptoacyl derivatives of substituted prolines such as any of thosedisclosed in U.S. Pat. No. 4,316,906 with zofenopril being preferred.

Other examples of mercapto containing ACE inhibitors that may beemployed herein include rentiapril (fentiapril, Santen) disclosed inClin. Exp. Pharmacol. Physiol. 10:131 (1983); as well as pivopril andYS980.

Other examples of angiotensin converting enzyme inhibitors which may beemployed herein include any of those disclosed in U.S. Pat. No.4,374,829 mentioned above, withN-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline, that is,enalapril, being preferred, any of the phosphonate substituted amino orimino acids or salts disclosed in U.S. Pat. No. 4,452,790 with(S)-1-[6-amino-2-[[hydroxy-(4-phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-L-prolineor (ceronapril) being preferred, phosphinylalkanoyl prolines disclosedin U.S. Pat. No. 4,168,267 mentioned above with fosinopril beingpreferred, any of the phosphinylalkanoyl substituted prolines disclosedin U.S. Pat. No. 4,337,201, and the phosphonamidates disclosed in U.S.Pat. No. 4,432,971 discussed above.

Other examples of ACE inhibitors that may be employed herein includeBeecham's BRL 36,378 as disclosed in European Patent Application Nos.80822 and 60668; Chugai's MC-838 disclosed in C.A. 102:72588v and Jap.J. Pharmacol. 40:373 (1986); Ciba-Geigy's CGS 14824(3-([1-ethoxycarbonyl-3-phenyl-(1S)-propyl]amino)-2,3,4,5-tetrahydro-2-oxo-1-(3S)-benzazepine-1acetic acid HCl) disclosed in U.K. Patent No. 2103614 and CGS 16,617(3(S)-[[(1S)-5-amino-1-carboxypentyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-ethanoicacid) disclosed in U.S. Pat. No. 4,473,575; cetapril (alacepril,Dainippon) disclosed in Eur. Therap. Res. 39:671 (1986); 40:543 (1986);ramipril (Hoechsst) disclosed in Euro. Patent No. 79-022 and Curr. Ther.Res. 40:74 (1986); Ru 44570 (Hoechst) disclosed in Arzneimittelforschung34:1254 (1985), cilazapril (Hoffman-LaRoche) disclosed in J. Cardiovasc.Pharmacol. 9:39 (1987); R 31-2201 (Hoffman-LaRoche) disclosed in FEBSLett. 165:201 (1984); lisinopril (Merck), indalapril (delapril)disclosed in U.S. Pat. No. 4,385,051; indolapril (Schering) disclosed inJ. Cardiovasc. Pharmacol. 5:643, 655 (1983), spirapril (Schering)disclosed in Acta. Pharmacol. Toxicol. 59 (Supp. 5):173 (1986);perindopril (Servier) disclosed in Eur. J. clin. Pharmacol. 31:519(1987); quinapril (Warner-Lambert) disclosed in U.S. Pat. No. 4,344,949and CI925 (Warner-Lambert)([3S-[2[R(*)R(*)]]3R(*)]-2-[2-[[1-(ethoxy-carbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylicacid HCl) disclosed in Pharmacologist 26:243, 266 (1984), WY-44221(Wyeth) disclosed in J. Med. Chem. 26:394 (1983).

Preferred ACE inhibitors are captopril, fosinopril, enalapril,lisinopril, quinapril, benazepril, fentiapril, ramipril and moexipril.

NEP/ACE inhibitors may also be employed herein in that they possessneutral endopeptidase (NEP) inhibitory activity and angiotensinconverting enzyme (ACE) inhibitory activity. Examples of NEP/ACEinhibitors suitable for use herein include those disclosed in U.S. Pat.Nos. 5,362,727, 5,366,973, 5,225,401, 4,722,810, 5,223,516, 4,749,688,U.S. Pat. No. 5,552,397, U.S. Pat. No. 5,504,080, U.S. Pat. No.5,612,359,U.S. Pat. No. 5,525,723, European Patent Application 0599,444,0481,522, 0599,444, 0595,610, European Patent Application 0534363A2,534,396 and 534,492, and European Patent Application 0629627A2.

Preferred are those NEP/ACE inhibitors and dosages thereof which aredesignated as preferred in the above patents/applications which U.S.patents are incorporated herein by reference; most preferred areomapatrilat, BMS 189,921([S—(R*,R*)]-hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid (gemopatrilat)) and CGS 30440.

The angiotensin II receptor antagonist (also referred to herein asangiotensin II antagonist or AII antagonist) suitable for use hereinincludes, but is not limited to, irbesartan, losartan, valsartan,candesartan, telmisartan, tasosartan or eprosartan, with irbesartan,losartan or valsartan being preferred.

A preferred oral dosage form, such as tablets or capsules, will containthe ACE inhibitor or AII antagonist in an amount within the range fromabut 0.1 to about 500 mg, preferably from about 5 to about 200 mg andmore preferably from about 10 to about 150 mg.

For parenteral administration, the ACE inhibitor, angiotensin IIantagonist or NEP/ACE inhibitor will be employed in an amount within therange from about 0.005 mg/kg to about 10 mg/kg and preferably from about0.01 mg/kg to about 1 mg/kg.

Where a drug is to be administered intravenously, it will be formulatedin conventional vehicles, such as distilled water, saline, Ringer'ssolution or other conventional carriers.

It will be appreciated that preferred dosages of ACE inhibitor and AIIantagonist as well as other antihypertensives disclosed herein will beas set out in the latest edition of the Physician's Desk Reference(PDR).

Other examples of preferred antihypertensive agents suitable for useherein include omapatrilat (Vanlev®) amlodipine besylate (Norvasc®),prazosin HCl (Minipress®), verapamil, nifedipine, nadolol, diltiazem,felodipine, nisoldipine, isradipine, nicardipine, atenolol, carvedilol,sotalol, terazosin, doxazosin, propranolol, and clonidine HCl(Catapres®).

Diuretics which may be employed in combination with compounds of formulaI include hydrochlorothiazide, torasemide, furosemide, spironolactono,and indapamide.

Antiplatelet agents which may be employed in combination with compoundsof formula I of the invention include aspirin, clopidogrel, ticlopidine,dipyridamole, abciximab, tirofiban, eptifibatide, anagrelide, andifetroban, with clopidogrel and aspirin being preferred.

The antiplatelet drugs may be employed in amounts as indicated in thePDR. Ifetroban may be employed in amounts as set out in U.S. Pat. No.5,100,889.

Antiosteoporosis agents suitable for use herein in combination with thecompounds of formula I of the invention include parathyroid hormone orbisphosphonates, such as MK-217 (alendronate) (Fosamax®). Dosagesemployed will be as set out in the PDR.

In carrying our the method of the invention, a pharmaceuticalcomposition will be employed containing the compounds of structure I,with or without another therapeutic agent, in association with apharmaceutical vehicle or diluent. The pharmaceutical composition can beformulated employing conventional solid or liquid vehicles or diluentsand pharmaceutical additives of a type appropriate to the mode ofdesired administration. The compounds can be administered to mammalianspecies including humans, monkeys, dogs, etc. by an oral route, forexample, in the form of tablets, capsules, granules or powders, or theycan be administered by a parenteral route in the form of injectablepreparations. The dose for adults is preferably between 50 and 2,000 mgper day, which can be administered in a single dose or in the form ofindividual doses from 1-4 times per day.

A typical capsule for oral administration contains compounds ofstructure I (250 mg), lactose (75 mg) and magnesium stearate (15 mg).The mixture is passed through a 60 mesh sieve and packed into a No. 1gelatin capsule.

A typical injectable preparation is produced by aseptically placing 250mg of compounds of structure I into a vial, aseptically freeze-dryingand sealing. For use, the contents of the vial are mixed with 2 mL ofphysiological saline, to produce an injectable preparation.

The following Examples represent preferred embodiments of the invention.

The following abbreviations are employed in the Examples:

-   Ph=phenyl-   Bn=benzyl-   t-Bu=tertiary butyl-   Me=methyl-   Et=ethyl-   TMS=trimethylsilyl-   TMSN₃=trimethylsilyl azide-   TBS=tert-butyldimethylsilyl-   FMOC=fluorenylmethoxycarbonyl-   Boc=tert-butoxycarbonyl-   Cbz=carbobenzyloxy or carbobenzoxy or benzyloxycarbonyl-   THF=tetrahydrofuran-   Et₂O=diethyl ether-   hex=hexanes-   EtOAc=ethyl acetate-   DMF=dimethyl formamide-   MeOH=methanol-   EtOH=ethanol-   i-PrOH=isopropanol-   DMSO=dimethyl sulfoxide-   DME=1,2 dimethoxyethane-   DCE=1,2 dichloroethane-   HMPA=hexamethyl phosphoric triamide-   HOAc or AcOH=acetic acid-   TFA=trifluoroacetic acid-   i-Pr₂NEt=diisopropylethylamine-   Et₃N=triethylamine-   NMM=N-methyl morpholine-   DMAP=4-dimethylaminopyridine-   NaBH₄=sodium borohydride-   NaBH(OAc)₃=sodium triacetoxyborohydride-   DIBALH=diisobutyl aluminum hydride-   LiAlH₄=lithium aluminum hydride-   n-BuLi=n-butyllithium-   Pd/C=palladium on carbon-   PtO₂=platinum oxide-   KOH=potassium hydroxide-   NaOH=sodium hydroxide-   LiOH=lithium hydroxide-   K₂CO₃=potassium carbonate-   NaHCO₃=sodium bicarbonate-   DBU=1,8-diazabicyclo[5.4.0]undec-7-ene-   EDC (or EDC.HCl) or EDCI (or EDCI.HCl) or    EDAC=3-ethyl-3′-(dimethylamino)propyl-carbodiimide hydrochloride (or    1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride)-   HOBT or HOBT.H₂O=1-hydroxybenzotriazole hydrate-   HOAT=1-Hydroxy-7-azabenzotriazole-   BOP reagent=benzotriazol-1-yloxy-tris(dimethylamino) phosphonium    hexafluorophosphate-   NaN(TMS)₂=sodium hexamethyldisilazide or sodium    bis(trimethylsilyl)amide-   Ph₃P=triphenylphosphine-   Pd(OAc)₂=Palladium acetate-   (Ph₃P)₄Pd^(o)=tetrakis triphenylphosphine palladium-   DEAD=diethyl azodicarboxylate-   DIAD=diisopropyl azodicarboxylate-   Cbz-Cl=benzyl chloroformate-   CAN=ceric ammonium nitrate-   SAX=Strong Anion Exchanger-   SCX=Strong Cation Exchanger-   Ar=argon-   N₂=nitrogen-   min=minute(s)-   h or hr=hour(s)-   L=liter-   mL=milliliter-   μL=microliter-   g=gram(s)-   mg=milligram(s)-   mol=moles-   mmol=millimole(s)-   meq=milliequivalent-   RT=room temperature-   sat or sat'd=saturated-   aq.=aqueous-   TLC=thin layer chromatography-   HPLC=high performance liquid chromatography-   LC/MS=high performance liquid chromatography/mass spectrometry-   MS or Mass Spec=mass spectrometry-   NMR=nuclear magnetic resonance-   NMR spectral data: s=singlet; d=doublet; m=multiplet; br=broad;    t=triplet-   mp=melting point

EXAMPLE 1

To a 0° C. solution of 4-hydroxybenzaldehyde (1.70 g, 12.3 mmol),5-phenyl-2-methyl-oxazole-4-ethanol (Maybridge; 2.50 g, 14.0 mmol) andPh₃P (4.20 g, 16.0 mmol) in dry THF (30 mL) was added dropwise DEAD(3.20 g, 15.0 mmol). The solution was stirred at 0° C. for 0.5 h, thenwas allowed to warm to RT and stirred overnight. The orange-red solutionwas concentrated in vacuo and the residue was chromatographed (stepwisegradient from 5:1 to 5:2 hex:EtOAc) to give Part A compound (2.47 g,65%) as a clear, slightly yellow viscous oil.

A1. Alternative Procedure for Preparing Part A Aldehyde

To a −5° C. solution of 5-phenyl-2-methyl-oxazole-4-ethanol (20.00 g,0.098 mol) in CH₂Cl₂ (100 mL) was added methanesulfonyl chloride (12.40g, 0.108 mol) in one portion (exothermic reaction). After recooling to−5° C., Et₃N (11.1 g, 0.110 mol) was added slowly over 30 min (internaltemperature<3° C.). The reaction was allowed to warm to RT and stirredfor 1 h (reaction monitored by analytical HPLC), at which point startingmaterial had been consumed. The reaction was washed with aqueous HCl(2×50 mL of a 3N solution). The combined aqueous layers were extractedwith CH₂Cl₂ (50 mL). The combined organic extracts were successivelywashed with satd. aqueous NaHCO₃ and brine (50 mL each), dried (Na₂SO₄),and concentrated to ˜30 mL volume. Methyl tert-butyl ether (120 mL) wasadded and the mixture was stirred; a white solid was formed. The mixturewas cooled to −20° C. for complete crystallization. The product wasfiltered and vacuum-dried to give the product mesylate (23.3 g, 85%) asa white solid. The mother liquor was concentrated in vacuo andrecrystallized from methyl tert butyl ether/heptane to give a secondcrop of product mesylate (3.3 g, 12%; total yield=97%).

A mixture of the above mesylate (13.6 g, 0.048 mol),4-hydroxybenzaldehyde (7.09 g, 0.058 mol) and K₂CO₃ (9.95 g, 0.072 mol)in DMF (110 mL) was heated at 100° C. for 2 h (reaction complete byanalytical HPLC). The mixture was allowed to cool to RT and then pouredinto ice-water (400 mL) and stirred for 30 min. The solid product wasfiltered and washed with cold water (3×25 mL) and dried in vacuo at50°-60° C. overnight. The crude product was crystallized fromMTBE-Hexane to give (12.2 g, 82%; 2 crops) the aldehyde (Part A1compound) as a white solid.

To a solution of N-benzyl glycine ethyl ester (43 mg; 0.22 mmol) andPart A1 compound (52 mg; 0.17 mmol) in DCE (10 mL) was added NaBH(OAc)₃(56 mg; 0.26 mmol). The reaction mixture was stirred vigorouslyovernight for 12 hours. Saturated aqueous NaHCO₃ (10 mL) was added, andthe mixture was extracted with EtOAc (3×10 mL). The combined organicextracts were washed with brine, dried (Na₂SO₄), concentrated in vacuoand chromatographed (hex:EtOAc 4:1) to give Part B compound (45 mg; 55%)as a pale yellow oil in addition to recovered starting material (14 mg;27%).

To a solution of Part B compound (45 mg) in MeOH (2 mL) was addedaqueous NaOH (3 mL of a 1M solution). The solution was stirred overnightfor 14 h and then acidified to pH 5 with excess aqueous HCl (1Msolution). The mixture was extracted with EtOAc (2×10 mL); the combinedorganic extracts were washed with brine, dried (Na₂SO₄), andconcentrated in vacuo to give the desired acid which was stillcontaminated with starting material. This mixture was dissolved in MeOH(2 mL) and aqueous NaOH (3.0 mL of a 1M solution) and the resultingsolution was refluxed for 1.5 h. Acidic extractive workup as above gavethe desired title compound as a colorless solid (28 mg; 71%).[M+H]⁺=457.2

EXAMPLE 2

To a solution of Example 1 Part A compound (147 mg; 0.479 mmol) andglycine ethyl ester hydrochloride (73 mg; 0.52 mmol) in DCE (2 mL) wasadded Et₃N and NaBH(OAc)₃ (156 mg; 0.74 mmol) and the reaction wasstirred overnight at RT. Flash chromatography (stepwise gradient from7:3 to 2:3 hex: EtOAc) gave 35 mg (21%) of the dibenzyl glycine ester(Example 2 Part A compound). In addition, 127 mg (67%) of the monobenzylglycine ester (Example 3 Part A compound) was obtained.

A solution of Example 1 Part A compound (35 mg; 0.051 mmol) in MeOH (2mL) and aqueous NaOH (3 mL of a 1M solution) was heated under reflux for12 h. The solution was adjusted to pH 5 with aqueous 1M HCl and aqueous1 M NaOH, then extracted with EtOAc (3×). The combined organic extractswere washed with brine, dried (Na₂SO₄), and concentrated in vacuo togive title compound (13 mg) as a colorless solid. [M+H]⁺=658.2

EXAMPLE 3

To a solution of Example 1 Part A compound (147 mg; 0.479 mmol) andglycine ethyl ester hydrochloride (73 mg; mmol) in DCE was added Et₃Nand NaBH(OAc)₃ (156 mg; 0.74 mmol). Flash chromatography (stepwisegradient from 7:3 to 2:3 hex: EtOAc) gave 127 mg (67%) of the titlecompound. In addition, 35 mg (21%) of the bis-benzyl glycine ester(Example 2 Part A compound) was obtained as a byproduct.

A solution of Part A compound (72 mg; 0.18 mmol) in aqueous NaOH (2 mLof a 1M solution) and MeOH (2 mL) was refluxed for 3 h. The reaction wasadjusted to pH 5 with aqueous 1M HCl, and solids were filtered off. Thefiltrate was extracted with EtOAc (3×). The combined organic extractswere washed with brine, dried (Na₂SO₄) and concentrated in vacuo to givea colorless solid, which was purified by preparative HPLC (utilizing aYMC S5 ODS 20 mm×100 mm column with a continuous gradient from 70% A:30%B to 100% B for 10 min at a flow rate of 20 mL/min, whereA=90:10:0.1H₂O:MeOH:TFA and where B=90:10:0.1 MeOH:H₂O:TFA) to givetitle compound (10 mg; 15%) as a colorless solid. [M+H]⁺=367.2

EXAMPLE 4

A solution of the amino t-butyl ester (0.040 g, 0.095 mmol), (preparedas described for Example 7 Part C, except that the aldehyde used in thereductive amination was Example 1 Part A instead of Example 7 Part A)

and propargyl bromide (0.014 g, 0.120 mmol) and DBU (0.5 mL; 2.96 mmol)in DCE (1 mL) was stirred at 0° C. for 5 h. TLC showed that the reactionwas complete at this point. EtOAc (10 mL) was added and the organicphase was washed with H₂O and concentrated in vacuo. The residual oilwas dissolved in CH₂Cl₂/TFA (1:1, 1 mL) and stirred at RT for 5 h, thenconcentrated in vacuo. The residue was purified by preparative HPLC (YMCS5 ODS 30 mm×250 mm reverse phase column; flow rate=25 mL/min; 30 mincontinuous gradient from 70:30 A:B to 100% B; whereA=90:10:0.1H₂O:MeOH:TFA and where B=90:10:0.1 MeOH:H₂O:TFA) to give thetitle compound (34 mg, 92%) as an oil. LC/MS (electrospray) gave thecorrect [M+H]-hu +=405.2 for the title compound.

EXAMPLE 5

A solution of 2-chlorobenzoxazole (20 mg; 0.131 mmol), the secondaryamine-methyl ester (52 mg; 0.146 mmol)

(prepared as described in Example 3 Part A except glycine ethyl esterHCl was replaced by glycine methyl ester HCl and the Example 7 Part Aaldehyde was employed), and excess Et₃N (0.5 mL) in THF (2.0 mL) washeated to 100° C. in a sealed tube and the reaction was monitored byLC/MS. After 4 days, starting amine had been consumed. The reaction wascooled to RT and aqueous LiOH (0.50 mL of a 1 M solution) was added tothe solution. The solution was stirred at RT for 5 h, after which thehydrolysis was complete. The mixture was concentrated in vacuo to givethe crude acid as an oil, which was purified by preparative HPLC (30 mincontinuous gradient from 70:30 A:B to 100% B, whereA=90:10:0.1H₂O:MeOH:TFA and B=90:10:0.1 MeOH:H₂O:TFA; flow rate=25mL/min; YMC S5 ODS 30×250 mm reverse-phase column) to give the titlecompound (52 mg; 82%) as a solid after lyophilization from (MeOH/H₂O).[M+H]⁺=484.2

EXAMPLE 6

The title compound (13 mg; 21%) was prepared in an analogous fashion toExample 5 using the corresponding secondary amine-methyl ester.

(This compound was prepared as described in Example 3 Part A exceptglycine ethyl ester HCl was replaced by glycine methyl ester HCl).Example 6: [M+H]⁺=484.2

EXAMPLE 7

To a 0° C. solution of 3-hydroxybenzaldehyde (3.00 g; 24.6 mmol),2-phenyl-5-methyl-oxazole-4-ethanol (5.00 g; 24.6 mmol) and Ph₃P (7.10g; 27.1 mmol) in dry THF (75 mL) was added dropwise DEAD (4.27 mL; 27.1mmol) over 10 min. The brown-orange solution was allowed to warm to RTand stirred at RT for 24 h. The solution was concentrated in vacuo andchromatographed (SiO₂; stepwise gradient: 100% hex to hex:EtOAc 3:1) togive Part A compound as a pale yellow viscous oil (4.01 g; 53%).

A.1. Alternative Procedure for Preparing Part A Aldehyde

To a solution of 3-hydroxybenzaldehyde (9.1 g; 0.074 mmol) in CH₃CN (206mL) was added K₂CO₃ (10.3 g). The mixture was heated to 90° C. in an oilbath and stirred for 18 h at 90° C. (the reaction was complete at thispoint by analytical HPLC). The reaction was cooled to RT, then dilutedwith EtOAc (500 mL), washed with H₂O, aqueous NaOH (2×100 mL of a 1 Msolution) and brine. The organic phase was dried (MgSO₄) andconcentrated in vacuo. The residual oil was chromatographed (SiO₂;hex:EtOAc from 9:1 to 4:1) to give the Part A aldehyde (12.7 g; 67%) asa viscous, clear, pale yellow oil.

A solution of the Part A1 compound (4.00 g; 13.0 mmol), glycinetert-butyl ester hydrochloride (2.40 g; 14.3 mmol) and Et₃N (2.18 mL;15.7 mmol) in MeOH (30 mL) was stirred at RT for 6 h and then cooled to0° C. A solution of NaBH₄ (594 mg; 15.7 mmol) in MeOH (10 mL) was addedportionwise at 0° C. to the solution of crude imine over ˜15 min. Thesolution was stirred at 0° C. for 3 h, then at RT for 3 h, thenconcentrated in vacuo without heating to removed MeOH. The residue waspartitioned between saturated aqueous NaCl and EtOAc (50 mL each). Theaqueous layer was extracted with EtOAc (2×50 mL). The combined organicextracts were dried (Na₂SO₄) and concentrated in vacuo to give a yellowoil, which was chromatographed on SiO₂ (stepwise gradient; hex:EtOAcfrom 4:1 to 2:3) to give Part B compound as a pale viscous yellow oil(4.82 g; 88%).

To a solution of Part B compound (0.400 g; 0.95 mmol) and4-phenoxybenzaldehyde (0.216 g; 1.09 mmol) in DCE (5 mL) was addedNaBH(OAc)₃ (0.300 g; 1.42 mmol), followed by HOAc (25 μL). The reactionwas stirred at RT for 24 h. 10% unreacted starting amine was stillpresent by analytical HPLC. Additional aldehyde (30 mg) and NaBH(OAc)₃(60 mg) were added and the reacton was stirred at RT for a further 18 h,after which reaction was complete. The solution was partitioned betweenaqueous NaHCO₃ (50 mL of a 10% solution) and EtOAc (50 mL). The aqueouslayer was extracted with EtOAc (2×25 mL). The combined organic extractswere washed with aqueous NaHCO₃ (2×15 mL of a 10% solution), dried(Na₂SO₄) and concentrated in vacuo to give Part C compound (521 mg crudematerial) as a clear, colorless oil.

Part C compound was dissolved in CHCl₃ (2 mL) and TFA (1.5 mL) and thesolution was stirred at RT for 24 h. The solution was concentrated invacuo and the residue was purified by preparative HPLC (YMC S5 ODS20×250 mm column; continuous gradient from 40:60 solvent A:B to 100%solvent B; where solvent A=90:10:0.1H₂O:MeOH:TFA; solvent B=90:10:0.1MeOH:H₂O:TFA). The purified product was lyophilized from MeOH/H₂O togive the title amino acid (312 mg; 48% over 2 steps) as its TFA salt(off-white lyophilate). [M+H]⁺(electrospray)=549.3

EXAMPLE 8

A mixture of the amino-ester (39 mg; 0.092 mmol),

(prepared as described in Example 4),2-naphthaldehyde (29 mg; 0.185 mmol), and NaBH(OAc)₃ (100 mg; 0.472mmol) in DCE (1.5 mL) was stirred at RT for 16 h. TFA (1.0 mL) was thenadded to the mixture, which was stirred at RT for a further 12 h.Volatiles were removed in vacuo. The resulting residue was diluted withMeOH (1.5 mL), filtered, and purified by preparative HPLC (YMC S5 ODS 30mm×250 mm column; continuous 30 min gradient @ 25 mL/min from 100% A to100% B; solvent A=90:10:0.1H₂O:MeOH:TFA; B=90:10:0.1 MeOH:H₂O:TFA) togive the desired title product (39 mg; 68%) as a clear, viscous oil.[M+H]⁺=507.3

EXAMPLE 9

A solution of the amino acid tert-butyl ester (1.8 g, 4.27 mmol)

(prepared as described in Example 7 Part B),and TFA (20 mL) in CH₂Cl₂ (40 mL) was stirred at RT overnight. Thesolution was concentrated in vacuo, and the residue was dissolved inCH₂Cl₂ and eluted through solid NaHCO₃ (to remove excess TFA) withexcess CH₂Cl₂. The combined filtrates were concentrated in vacuo toprovide the desired amino acid Part A compound (1.48 g; 95%).[M+H]⁺=457.2

The title compound was prepared as part of a solution phase library runusing the following exemplary procedure:

To a solution of the Part A amino acid compound (27 mg, 0.074 mmol; in 2mL CH₂Cl₂) was added (4-chloro-phenoxy)-3-benzaldehyde (86 mg; 0.37mmol), NaBH(OAc)₃ (79 mg, 0.37 mmol) and HOAc (0.1 mL). The reaction wasstirred at RT for 15 h.

The product was purified via solid-phase extraction using a Varian SAXcartridge (3 g of sorbent in a 6 mL column, 0.3 meq/g) by the procedureoutlined below:

-   1) The column was conditioned with MeOH (10 mL) and CH₂Cl₂ (20 mL)-   2) The reaction mixture was loaded onto the SAX column-   3) The column was rinsed with CH₂Cl₂ (10 mL)-   4) The column was rinsed with 1% TFA in MeOH (3 mL)-   5) The product was eluted with 1% TFA in MeOH (20 mL)

The product solution (combined fractions from step 5) was concentratedusing a Speed Vac for 16 h to afford the crude product (25 mg; 49%) as asolid. Reverse-phase HPLC analysis (YMC S5 ODS 4.6×33 mm column,continuous gradient from 100% A to 100% B for 2 min at a flow rate of 5mL/min [Solvent A=10% MeOH/90% H₂O/0.2% H₃PO₄; Solvent B=90% MeOH/10%H₂O/0.2% H₃PO₄]) indicated that the product purity was 92%. In addition,LC/MS (electrospray) gave the correct molecular ion [(M+H)⁺=583] for thetitle compound.

EXAMPLE 10

(Procedure used with heterocyclic aldehydes)

The title compound was prepared as part of a solution phase library runusing the following exemplary procedure.

A mixture of the amino acid (14 mg; 0.038 mmol),

(prepared as described in example 9 part a),5-(4-chlorophenyl)-2-furfural (16 mg; 0.076 mmol), and NaBH(OAc)₃ (72mg; 0.34 mmol) in DCE (1.5 mL) was stirred at RT for 16 h. TFA (1.0 mL)was then added to the mixture, which was stirred at RT for a further 12h. Volatiles were removed in vacuo. The resulting residue was dilutedwith MeOH (1.5 mL), filtered, and purified by preparative HPLC (YMC S5ODS 30 mm×250 mm column; continuous 30 minute gradient @ 25 mL/min from100% A to 100% B; solvent A=90:10:0.1H₂O:MeOH:TFA; B=90:10:0.1MeOH:H₂O:TFA) to give the desired title product (39 mg; 68%) as a clear,viscous oil.

EXAMPLE 10A

An alternative purification procedure to preparative HPLC was used asfollows:

The crude reductive amination product was purified by solid-phaseextraction using an SAX cartridge (United Chemicals; 3 g of sorbent in a6 mL column, 0.3 meq/g) by the procedure outlined below:

-   1) The column was conditioned with MeOH (5 mL) and CH₂Cl₂ (5 mL)-   2) The reaction mixture (diluted with 2 mL CH₂Cl₂) was loaded onto    the SAX column-   3) The column was rinsed with CH₂Cl₂ (8 mL)-   4) The product was eluted with 1% TFA in MeOH (20 mL)

The product-containing fractions were concentrated in vacuo using aSpeed Vac for 16 h to afford the crude product. This was dissolved inCH₂Cl₂:MeOH (95:5) and loaded onto a silica gel cartridge (1.5 g SiO₂)and the product was eluted with CH₂Cl₂:MeOH (95:5; 8 mL). Theproduct-containing fractions were concentrated in vacuo using a SpeedVac to give the desired title product.

Reverse Phase HPLC analysis (YMC S5 ODS 4.6×33 mm column, continuousgradient from 100% A to 100% B for 2 min at a flow rate of 5 mL/min[Solvent A=10% MeOH/90% H₂/0.2% H₃PO₄; Solvent B=90% MeOH/10% H₂O/0.2%H₃PO₄]) indicated that the product purity was 92%. In addition, LC/MS(electrospray) gave the correct molecular ion [(M+H)⁺=583] for titlecompound.

EXAMPLE 11

To a mixture of the amino-tert-butyl ester (0.339 g, 0.80 mmol),

(prepared as described in Example 7, Part B),4-hydroxybenzaldehyde (0.127 g, 1.03 mmol) and NaBH(OAc)₃ (0.510 g, 2.4mmol) was added 7 drops of HOAc. The reaction was stirred at RT for 16h. The mixture was diluted with EtOAc, then washed with aqueous NaHCO₃.The organic phase was dried (MgSO₄) and concentrated in vacuo. The crudeproduct was chromatographed (SiO₂; hexanes/EtOAc 3:1 to 1:4) to providethe 4-hydroxybenzyl amino ester title compound compound (0.381 g, 90%).

The title compound was prepared as part of a solution phase library runusing the following exemplary procedure.

To a solution of Part A phenol compound (30 mg, 0.057 mmol) in CH₂Cl₂ (1mL) was added 3-fluorophenyl boronic acid (12 mg; 0.086 mmol) and 4Amolecular sieves (pre-dried at 400° C. overnight) at RT. After stirringfor 5 min, Cu(OAc)₂ (1 eq), Et₃N (5 eq) and pyridine (5 eq) were addedto the mixture. The vial was capped and air was allowed to pass into thereaction. The reaction was stirred at RT for 60 h and was complete byanalytical HPLC and LC/MS. (For other reactions which were incompleteafter this time, additional boronic acid (1.5 equivalent) was added inorder to form additional desired product). The reaction mixture wasfiltered and concentrated in vacuo.

The product was purified via solid-phase extraction using a UnitedTechnology SCX column (2 g of sorbent in a 6 mL column) by the procedureoutlined below.

-   1) The column was conditioned with MeOH (10 mL) and CH₂Cl₂ (10 mL)-   2) The residue was dissolved in a minimal volume of CH₂Cl₂ and    loaded onto the SCX column.-   3) The cartridge was successively washed with CH₂Cl₂ (20 mL),    CH₂Cl₂/MeOH (20% MeOH, 20 mL) and MeOH (20 mL)-   4) The product was eluted with a solution of 0.5N NH₃ in MeOH.

The product-containing fractions were concentrated in vacuo to give thedesired tert-butyl ester. (Some incomplete reactions requiredchromatography (on SiO₂) of the crude material to give esters of therequisite purity). The t-butyl ester was treated with a solution of 30%TFA in CH₂Cl₂ overnight. Volatiles were removed and the residue wasredissolved in CH₂Cl₂ (1 mL) and concentrated in vacuo on a Speed Vac toafford the desired title product (30 mg; 77%). Reverse phase HPLCanalysis indicated that the product purity was 90%. In addition LC/MSgave the correct molecular ion [(M+H)⁺=567] for the desired titlecompound.

EXAMPLE 12

To a solution of the secondary amine-tert butyl ester (110 mg; 0.26mmol)

(prepared as described in Example 7, Part B),in 1,2-dichloroethane (4 mL) were successively added 4-formylphenylboronic acid (47 mg; 0.31 mmol) and NaBH(OAc)₃ (165 mg; 0.78mmol). The mixture was stirred at RT for 3 h. Analytical HPLC and LC/MSindicated that the reaction was complete at this point. Volatiles wereremoved in vacuo and the residue was chromatographed (SiO₂; stepwisegradient from 3:1 to 1:1 hexane:EtOAc) to provide title compound (133mg; 91%) as a white foam.

The title compound was prepared as part of a solution phase library runusing the following procedure.

To a solution of the Part A boronic acid compound (40 mg, 0.072 mmol) inCH₂Cl₂ (1 mL) was added m-cresol (23 mg; 0.22 mmol) and 4A molecularsieves (150 mg; pre-dried at 400° C. overnight). After stirring for 5min, Cu(OAc)₂ (1 eq), Et₃N (5 eq) and pyridine (5 eq) were added to themixture. The vial was capped and air was allowed to pass into thereaction, which was stirred at RT for 24 h. The reaction mixture wasfiltered through a pad of Celite and concentrated in vacuo.

The product was purified via solid-phase extraction using a UnitedTechnology SCX column (2 g of sorbent in a 6 mL column) by the procedureoutlined below.

-   1) The column was conditioned with MeOH (10 mL) and CH₂Cl₂ (10 mL)-   2) The residue was dissolved in a minimal volume of CH₂Cl₂ and    loaded onto the SCX column.-   3) The cartridge was successively washed with CH₂Cl₂ (20 mL) and    MeOH (20 mL).-   4) The product was eluted with a solution of 0.5N NH₃ in MeOH.-   5) The product-containing fractions were concentrated in vacuo-   6) The residue was dissolved in a minimum amount of CH₂Cl₂ and    loaded onto a silica gel cartridge (2 mL)-   7) The cartridge was eluted with hexane:EtOAc (3:1; 20 mL)-   8) The product-containing fractions were collected and concentrated    in vacuo to give the purified tert-butyl ester

The t-butyl ester was treated with a solution of 1:1 TFA in CH₂Cl₂overnight. Volatiles were removed and the residue was redissolved inCH₂Cl₂ (1 mL) and concentrated in vacuo on a Speed Vac to afford thedesired title product (25 mg; 48%) as a slightly yellowish oil. Reversephase HPLC analysis indicated that the product purity was 91%. Inaddition LC/MS gave the correct molecular ion [(M+H)⁺=563.2] for thedesired compound.

EXAMPLE 13

The title compound was prepared as part of a solution phase library runusing the following exemplary procedure.

To a solution of 3-bromopyridine (32 mg; 0.2 mmol) in DME (1 mL) weresuccessively added (Ph₃P)₄Pd (5 mg; 0.05 mol equiv) and the Example 12Part A boronic acid (50 mg; 0.09 mmol)

Finally, aqueous Na₂CO₃ (19 mg in 0.3 mL H₂O) was added and the mixturewas heated in an oil bath at 85° C. for 5 h; LC/MS indicated that thereaction was complete at this point.

The reaction mixture was filtered and the filtrate was chromatographedon a silica gel cartridge (2 mL; EtOAc). The product-containingfractions were concentrated in vacuo and the residue was chromatographedon another silica gel cartridge (2 mL; stepwise gradient of hexanes,hex:EtOAc 3:1 and EtOAc). The product-containing fractions wereconcentrated in vacuo and the residue was eluted through an SCX (2 g)cartridge (20 mL each of CH₂Cl₂ and MeOH; then product eluted with 2Mammonia in MeOH). The product-containing fractions were concentrated invacuo to give the desired biaryl amine tert-butyl ester product. Thiswas treated with a solution of CH₂Cl₂/TFA (7:3; 1 mL) overnight for 14h. Volatiles were removed to give title compound (39 mg; 67%) as an oil.[M+H]⁺=534.3

EXAMPLES 14 to 124

Following one of the above procedures, the following compounds of theinvention were prepared:

TABLE 1

Example No. R³ [M + H]⁺ 14

457.3 15

471.3 16

485.3 17

617.2 18

549.3 19

533.3 20

557.3 21

617.3 22

562.7 23

579.3 24

559.4 25

615.3 26

503.4 27

563.4 28

596.3 29

555.3 30

473.4 31

475.4 32

599.3 33

517.4 34

507.1 35

507.1 36

496.1 37

557.1 38

591.2 39

568.2 40

625.2 41

591.2 42

568.2 43

622.3 44

601.2 45

557.2 46

519.2 47

675.2 48

519.2 49

600.3 50

564.2 51

545.3 52

625.2 53

563.3 54

632.3 55

556.3 56

563.3 57

593.2 58

562.2 59

582.2 60

582.2 61

593.2 62

593.2 63

571.2 64

611.2 65

537.3 66

537.3 67

636.2

TABLE 2

Ex- ample No. R³ [M + H]⁺ 68

534.2 69

547.2 70

465.4 71

533.3 72

473.3 73

507.3 74

587.4 75

517.3 76

549.3 77

549.3 78

583.2 79

617.2 80

563.2 81

559.2 82

615.2 83

629.1 84

605.3 85

563.2 86

596.2 87

549.3 88

635.3 89

639.2 90

583.2 91

563.2 92

635.3 93

583.2 94

617.2 95

617.1 96

567.2 97

555.1 98

595.3 99

555.2 100

617.2 101

594.2 102

548.2 103

523.3 104

534.4 105

576.2 106

601.1 107

563.2 108

609.2 109

551.2 110

523.2 111

539.2 112

579.3 113

594.4 114

563.3 115

583.2 116

579.3 117

583.2 118

594.3 119

594.3 120

537.3 121

537.3 122

535.2 123

535.2 124

496.1

EXAMPLE 125

A solution of Example 7 Part A aldehyde (60 mg; 0.20 mmol) and(S)-α-methyl benzylamine (30 mg; 0.24 mmol) in MeOH (1 mL) was stirredat RT for 6 h. The solution was cooled to 0° C. and a pre-formedsolution of NaBH₄ (9 mg; 0.24 mmol) in MeOH (0.5 mL) was addedportionwise. The reaction was stirred at RT overnight, then concentratedin vacuo without heating. The residue was partitioned between aqueousNaHCO₃ and EtOAc (5 mL each). The aqueous layer was extracted with EtOAc(2×5 mL). The combined organic extracts were dried (Na₂SO₄) andconcentrated in vacuo to give title compound as an orange yellow-oil (81mg crude).

A solution of the Part A compound (70 mg; 0.17 mmol), tert-butylbromoacetate (66 mg; 0.34 mmol), and iPr₂NEt in DMF (0.5 mL) was stirredat RT for 2 days. LC/MS showed that the reaction was complete and clean.The crude reaction mixture was partitioned between H₂O (30 mL) and EtOAc(20 mL). The aqueous layer was extracted with Et₂O (2×10 mL); thecombined organic extracts were dried (MgSO₄) and concentrated in vacuoto give the crude amino-tert-butyl ester.

This crude product was stirred in a 1:1 solution of CHCl₃ and TFA (2 mL)for 18 h at RT. The solution was then concentrated in vacuo and purifiedby preparative reverse-phase HPLC (as in Example 10). The purifiedmaterial was lyophilized from MeOH—H₂O to give the title compound (71mg; 71%) as a white lyophilate. [M+H]⁺=471.2

EXAMPLE 126

The title compound was synthesized following the same procedure asdescribed above in Example 125 except that (S)-α-methyl benzylamine wasreplaced by (R)-α-methyl benzylamine in the synthesis of the part Acompound. The title compound was obtained in 67% yield (66 mg) overall.[M+H]⁺=471.2

EXAMPLE 127

A mixture of Example 7 Part A compound (30 mg, 0.098 mmol), D-alaninetert-butyl ester hydrochloride (23 mg; 0.127 mmol), Et₃N (5 drops) and4A molecular sieves in MeOH (2 mL) was stirred at RT for 4 h. NaBH₄ (12mg, 0.0294 mmol) was added and the reaction was stirred at RT for 30min. The reaction mixture was then concentrated in vacuo, diluted withCH₂Cl₂ (2 mL), and filtered through cotton. TFA (1 mL) was added to thefiltrate and the reaction was stirred at RT overnight. The reactionmixture was concentrated in vacuo, diluted with EtOAc, washed severaltimes with sat'd. aqueous NaHCO₃, then with brine. The organic phase wasdried (MgSO₄) and concentrated in vacuo. The residue was purified bypreparative HPLC (YMC ODS 30 mm×250 mm reverse-phase column; flowrate=25 mL/min; 30 min continuous gradient from 50:50 A:B to 100% B,where A=90:10:0.1H₂O:MeOH: TFA and B=90:10:0.1 MeOH:H₂O:TFA) to providethe title compound (7.8 mg, 21%) as a white lyophilate. [M+H]⁺=381.1

EXAMPLE 128

Title compound (20% overall yield) was synthesized using the sameprocedure as described in Example 125, using D-phenylalanine tert-butylester hydrochloride instead of D-alanine tert-butyl ester hydrochloride.[M+H]⁺=457.2

EXAMPLE 129

A mixture of Example 7 Part A (40 mg, 0.13 mmol), D-alanine tert-butylester hydrochloride (31 mg, 0.17 mmol), Et₃N (6 drops) and 4A molecularsieves in MeOH (2 mL) was stirred at RT for 4 h. NaBH₄ (15 mg, 3 equiv)was added and the mixture was stirred at RT for 30 min, thenconcentrated in vacuo. The residue was dissolved in CH₂Cl₂ (2 mL) andfiltered. To the filtrate in a vial were added 4-phenoxybenzaldehyde (77mg, 0.39 mmol) and NaBH(OAc)₃ (138 mg, 0.65 mmol). The reaction wasstirred at RT for 18 h. The reaction mixture was chromatographed on SiO₂using hexanes/EtOAc (9:1 to 4:1) to obtain the pure tert-butyl ester.This material was dissolved in CH₂Cl₂ (2 mL) and TFA (1 mL) was addedslowly. The solution was stirred at RT overnight, then was concentratedin vacuo. The residue was redissolved in CH₂Cl₂ and filtered throughsolid NaHCO₃ to remove residual TFA. This solution was further dilutedwith CH₂Cl₂, washed with 1 M aq NaHSO₄ and brine, dried (MgSO₄),filtered and concentrated in vacuo to obtain the title compound (9.1 mg,12%). [M+H]⁺=563.2

EXAMPLE 130

The title compound (13% overall yield) was synthesized using the sameprocedure as described in Example 127, using D-phenyl-alanine tert-butylester hydrochloride instead of D-alanine tert-butyl ester hydrochloride.[M+H]⁺=639.2

EXAMPLES 131 to 135

Other analogs in this series were prepared by analogous procedures andare shown in the following table:

Example No. R^(3c) [M + H]⁺ 131 (S)—CH₃ 563.2 132

639.3 133

591.4 134

579.3 135

635.4

EXAMPLE 136

A solution of the secondary amine ethyl ester (72 mg; 0.183 mmol)

(prepared as described in Example 3 Part A) in MeOH (2 mL) and aqueousNaOH (2 mL of a 1M solution) was heated under reflux for 12 h. The pH ofthe solution was adjusted to 5 (with aqueous 1M NaOH and 1M HCl), uponwhich a colorless solid precipitated. This was filtered off and thefiltrate was extracted with EtOAc (3×); the combined organic extractswere dried (Na₂SO₄) and concentrated in vacuo to give the crude titleamino acid as a colorless solid (97 mg).

To a solution of the Part A amino acid (15 mg; 0.04 mmol) in dioxane:H₂O(1:1, 8 mL) was added K₂CO₃ (22 mg; 0.16 mmol) followed by benzylchloroformate (15 mg; 0.09 mmol). The reaction was stirred overnight,then concentrated in vacuo and acidified with excess aqueous 1M HCl.This was extracted with EtOAc (3×); the combined organic extracts werewashed with brine, dried (Na₂SO₄), and concentrated in vacuo to givetitle compound (13 mg; 63%) as a colorless solid. [M+H]⁺=501.3

EXAMPLE 137

To a 0° C. solution of the amino-tert-butyl ester (75 mg; 0.18 mmol)

(prepared as described in Example 7 Part B),in CH₂Cl₂ (1 mL) was added CbzCl (28 μL; 0.20 mmol), followed by Et₃N(54 μL; 0.39 mmol). The reaction was allowed to warm to RT and thenstirred at RT overnight for 18 h. Aqueous NaHCO₃ (2 mL of a 10%solution) was added and the aqueous layer was extracted with EtOAc (2×2mL). The combined organic extracts were dried (Na₂SO₄) and concentratedin vacuo. The crude carbamate-ester was dissolved in CHCl₃ (3 mL) andTFA (1 mL); the solution was stirred at RT for 24 h, then concentratedin vacuo. The crude carbamate-acid was purified by reverse-phasepreparative HPLC on a C-18 column (continuous gradient over 14 min; 4min hold time; flow rate=20 mL/min from 1:1 A:B to 100% B; solventA=90:10:0.1H₂O:MeOH:TFA; solvent B=90:10:0.1 MeOH:H₂O:TFA). The productwas lyophilized from MeOH/H₂O to give title compound as a whitelyophilate. [M+H]⁺=501.3.

EXAMPLE 138

A. The required aryl chloroformates (where not commercially available)were prepared according to the following general procedure, which isexemplified by the synthesis of 2-methoxy phenyl chloroformate:

A solution of 2-methoxyphenol (2 g, 16.1 mmol), N,N-dimethylaniline(1.95 g, 16.1 mmol), phosgene (8.34 mL of a 1.93 M solution in toluene,16.1 mmol) and a catalytic amount of DMF in chlorobenzene (5 mL) wasstirred in a pressure tube for 2 h at 80° C. The organic layer wasseparated and concentrated in vacuo. The residue was distilled (BuchiKugelrohr; bp=115° C. @ 10 mm Hg) to provide 2-methoxyphenylchloroformate (1.5 g; 50%) as a clear oil.

A solution of the amino-t-butyl ester (20 mg, 0.05 mmol),

(prepared as described in Example 7 Part B),2-methoxyphenyl chloroformate (8 mg, 0.05 mmol; prepared as above) andpolyvinylpyridine (Aldrich; 16 mg, 0.3 mmol) in CH₂Cl₂ (1 mL) wasstirred for 30 min at RT. Amine resin WA21J (Supelco; 200 mg) was addedand the mixture was stirred at RT for 30 min in order to removeunreacted chloroformate. The reaction mixture was filtered andconcentrated in vacuo to give the desired 2-methoxyphenylcarbamate-ester.

The ester was treated with a solution of 30% TFA in CH₂Cl₂ (5 mL)overnight. Volatiles were removed in vacuo to give the crude acid. Thismaterial was purified via solid-phase extraction using an anion exchangecolumn (CHQAX13M6 column; United Technologies; 3 g of sorbent in a 6 mLcolumn) by the exemplary procedure outlined below.

-   1) The column was conditioned with MeOH (10 mL) and CH₂Cl₂ (10 mL).-   2) The crude acid was dissolved in a minimal volume of CH₂Cl₂ and    loaded onto the SAX column.-   3) The cartridge was washed with CH₂Cl₂ (10 mL), CH₂Cl₂/MeOH (10 mL    of a 4:1 CH₂Cl₂:MeOH solution).-   4) The product was eluted with CH₂Cl₂/MeOH (10 mL of a 4:1    CH₂Cl₂:MeOH solution).

The product-containing fractions were concentrated in vacuo on a SpeedVac to afford title compound as an oil. Analytical reverse-phase HPLC(standard conditions) indicated that the purity of the product was 90%.In addition LC/MS gave the correct molecular ion [(M+H)⁺=517.3] for thedesired title compound.

EXAMPLE 139

Phosgene (0.21 mL of a 1.93 M solution in toluene; 0.40 mmol) was addeddropwise to a solution of the amino-tert-butyl ester (100 mg, 0.24 mmol)

(prepared as described in Example 7 Part B),and Et₃N (30.3 mg; 0.30 mmol) in 3 ml CH₂Cl₂ at −5° C. The reactionmixture was stirred at RT for 2 h. The mixture was concentrated in vacuoto give the crude product which was chromatographed (SiO₂; hexane/EtOAc1:5) to provide title compound (0.105 g, 91%).

The title compound was prepared as part of a solution phase library runusing the following exemplary procedure.

A mixture of the Part A carbamoyl chloride (20 mg; 0.045 mmol),3,5-dichlorophenol (16 mg; 0.07 mmol), and pyridine (0.5 ml) was stirredat 80° C. for 16 h. Pyridine was removed in vacuo and the residue waspurified via solid-phase extraction using a CHQAX1 cartridge (2 g ofsorbent in a 6 ml column, 0.3 mg/g) by the procedure outlined below:

-   1) The column was conditioned with MeOH (10 mL) and CH₂Cl₂(20 mL)-   2) The reaction mixture in CH₂Cl₂ was loaded onto the SAX column-   3) The product was eluted with CH₂Cl₂ (10 mL)

The product-containing fractions were concentrated in vacuo using aSpeed Vac over 16 h to afford the pure aryl carbamate-tert-butyl esterwhich was treated with a solution of 30% TFA in CH₂Cl₂ overnight.Volatiles were removed using a Speed Vac for 16 h to afford the crudeacid final product. The product was initially purified via solid-phaseextraction using a Varian SAX cartridge (2 g of sorbent in a 6 mLcolumn, 0.3 meq/g) by the procedure outlined below:

-   1) The column was conditioned with MeOH (10 mL) and CH₂Cl₂ (20 mL)-   2) The reaction mixture in CH₂Cl₂ was loaded onto the SAX column-   3) The column was rinsed with CH₂Cl₂ (10 mL)-   4) The column was rinsed with 10% MeOH in CH₂Cl₂ (10 mL)-   5) The product was eluted with 2% TFA in CH₂Cl₂ (10 mL)

The product-containing fractions were concentrated in vacuo using aSpeed Vac for 16 h to afford the purified product (20 mg, 80%) as asolid. Reverse phase HPLC analysis (YMC S5 ODS 4.6×33 mm column,continuous gradient from 50% A to 100% B for 2 min at a flow rate of 5mL/min [Solvent A=10% MeOH/90% H₂O/0.2% H₃PO₄; Solvent B=90% MeOH/10%H₂O/0.2% H₃PO₄]) indicated that the product purity was 96%. In addition,LC/MS gave the correct molecular ion [(M+H)⁺=555.2] (electrospray) forthe title compound.

EXAMPLE 140

Benzyl chloroformates were synthesized by the following generalprocedure, as exemplified by m-methoxy benzyl chloroformate:

To a solution of 3-methoxybenzyl alcohol (2.0 g; 7.24 mmol),N,N-dimethylaniline (0.877 g; 7.24 mmol) in anhydrous ether (5 mL) wasadded phosgene dropwise (3.8 mL of a 1.93 M solution in toluene; 7.3mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 h, afterwhich solids were filtered off. The filtrate was concentrated in vacuoat RT. The crude chloroformate was stripped from anhydrous Et₂O (2×2 mL)and used without further purification in the next reaction. Subsequentlyother chloroformates were also prepared using this standard procedure.

The title compound was prepared as part of a solution phase librarywhich was run using the following standard procedure.

To a suspension of the Example 3 amino acid (trifluoroacetic acid salt)

(25 mg, 0.05 mmol) in CH₂Cl₂ (1 mL) was added Part A compound (10 mg;0.05 mmol) and iPr₂NEt (19.4 mg; 0.15 mmol). After stirring for 30 minat RT, the reaction mixture was concentrated in vacuo.

The product was purified via solid-phase extraction using a VarianCHQAX13M6 (anion exchange) column (3 g of sorbent in a 6 mL column) bythe procedure outlined below:

-   1) The column was conditioned with MeOH (10 mL) and CH₂Cl₂ (10 mL)-   2) The residue was dissolved in a minimal volume of CH₂Cl₂ and    loaded onto the SAX column.-   3) The cartridge was washed successively with CH₂Cl₂ (10 mL), 20%    MeOH/CH₂Cl₂ (10 mL).-   4) The product was eluted with a solution of 20% MeOH/CH₂Cl₂ (10    mL).

The product-containing fractions were concentrated in vacuo using aSpeed Vac to afford the title compound. Reverse Phase HPLC analysisusing standard conditions indicated that the product purity was 90%. Inaddition, LC/MS (electrospray) gave the correct molecular ion[(M+H)⁺=531.3] for the desired title compound.

EXAMPLE 141

A solution of 4-(benzyloxy)phenol (2.0 g; 9.99 mmol),N,N-dimethylaniline (1.21 g; 9.99 mmol), phosgene (5.2 mL of a 1.95 Msolution in toluene; 10 mmol) and a catalytic amount of DMF inchlorobenzene (5 mL) was heated at 80° C. in a pressure tube for 2.5 h.The mixture was allowed to cool to RT. The upper clear solution wasseparated and concentrated in vacuo to give the crude title arylchloroformate as crystals (2 g crude product).

To a mixture of the Part A chloroformate (184 mg, 0.70 mmol) in CH₂Cl₂(5 mL) and polyvinylpyridine (Aldrich; 315 mg, 1 mmol) was added asolution of the amino-tert-butyl ester (280 mg, 0.66 mmol)

(prepared as described in Example 7 Part B),in CH₂Cl₂ (5 mL). The reaction was stirred at RT for 15 min. Resin-boundamine (WA21J, Supelco; 150 mg) was added to the mixture. The reactionmixture was stirred for another 15 min. The resin-bound amine andpolyvinylpyridine were filtered off and the filtrate was concentrated invacuo to give the crude product. The crude product was chromatographed(SiO₂; hexane/EtOAc 1:4) to provide title compound (0.30 g, 70%).

A solution of Part B compound (75 mg; 0.42 mmol) in 20 ml MeOH washydrogenated in the presence of 20 mg of 10% Pd/C under an atmosphere ofH₂ (balloon) for 24 h. The palladium catalyst was removed by filtrationand the filtrate was concentrated in vacuo to give the crude titlet-butyl ester (240 mg, 90%) which was used without further purificationin the next step.

The solution of Part C phenol-tert-butyl ester (50 mg; 0.089 mmol),catalytic Bu₄NBr (1.5 mg, 0.0047 mmol), aq NaOH (0.7 mL of a 1 Msolution) and isopropanol (2 mL) in a pressure tube was cooled to −50°C. Freon gas was bubbled into the solution for 1 min. The tube wassealed and heated to 80° C. for 12 h. The mixture was extracted withEtOAc (3×10 mL). The combined organic extracts were washed with brine,dried (Na₂SO₄) and concentrated in vacuo to give an oil, which was thentreated with a solution of 30% TFA in CH₂Cl₂ overnight. Volatiles wereremoved in vacuo and the residue was purified using preparative HPLC(YMC S5 ODS 30×250 mm reverse phase column; 30 minute continuousgradient from 70:30 A:B to 100% B, where A=90:10:0.1H₂O:MeOH:TFA, andB=90:10:0.1 MeOH:H₂O:TFA) to afford the desired title product (14 mg;28%). Reverse Phase HPLC analysis indicated that the product purity was97%. In addition LC/MS (electrospray) gave the correct molecular ion[(M+H)⁺=553.1] for the desired compound.

EXAMPLE 142

Following the Example 141 procedure, the analogous compound was prepared[(M+H)⁺=553.2]:

Intermediates corresponding to Example 141 Parts B and C weredeprotected using the same TFA/CHCl₃ procedure as above and purified asusual to give the following analogs:

EXAMPLES 145 to 305

The following carbamate-acid analogs in Tables 4 and 5 were synthesizedaccording to one of the above methods:

TABLE 4

Example No. R^(3d) [M + H]⁺ 145

487.2 146

539.3 147

593.2 148

449.3 149

501.3 150

517.2 151

532.2 152

589.3 153

546.3 154

532.2 155

579.2 156

593.2 157

593.3 158

579.2 159

579.2 160

531.2 161

527.2 162

525.2 163

515.2 164

529.2 165

527.2 166

519.3 167

517.3 168

547.3 169

577.3 170

531.3 171

531.3 172

545.3 173

531.3 174

571.2 175

567.3 176

547.3 177

545.3 178

579.2 179

591.2 180

535.2 181

505.2 182

521.1 183

566 + 588 184

571.1 185

505.2 186

521.1 187

566 + 588 188

545.2 189

529.1 190

529.1 191

543.1 192

571.2 193

503.3 194

501.3 195

529.4 196

531.3 197

561.3 198

555.3 199

513.3 200

557.4 201

543.3 202

571.4 203

572.3 204

541.3 205

543.4 206

529.4 207

515.3 208

515.3 209

515.3 210

543.3 211

529.4 212

577.3 213

515.3 214

529.3 215

527.3 216

531.3 217

557.3 218

573.1 219

519.2 220

535.2 221

585.2 222

519.2 223

535.2 224

585.2 225

561.2

TABLE 5

Example No. R^(3d) [M + H]⁺ 226

545.2 227

593.1 228

449.2 229

501.2 230

517.2 231

532.2 232

487.3 233

546.3 234

532.2 235

579.2 236

593.2 237

593.3 238

579.2 239

579.2 240

531.2 241

527.2 242

525.2 243

515.2 244

529.2 245

527.2 246

517.3 247

517.3 248

547.3 249

577.3 250

543.1 251

531.3 252

545.3 253

531.3 254

571.2 255

567.3 256

547.3 257

545.3 258

593.4 259

503.2 260

579.2 261

505.2 262

521.1 263

566/567 264

571.1 265

505.2 266

521.1 267

  566/567.0 268

523.3 269

501.3 270

539.2 271

529.3 272

549.2 273

523.2 274

513.3 275

519.2 276

539.2 277

547.3 278

552.3 279

541.3 280

563.3 281

555.3 282

543.3 283

529.3 284

515.3 285

515.3 286

515.3 287

535.2 288

529.2 289

577.3 290

515.2 291

529.2 292

527.3 293

537.3 294

531.3 295

555.2 296

571.3 297

573.2 298

531.3 299

519.3 300

535.2 301

585.2 302

519.2 303

535.2 304

585.2 305

561.2

EXAMPLE 149

To a solution of the secondary amine-ester (2.1 g; 5.52 mmol)

in CH₂Cl₂ (10 mL) was added 4-methylphenyl chloroformate (0.79 mL; 5.52mmol) and polyvinyl pyridine (Aldrich; 1.74 g; 16.5 mmol). The mixturewas stirred at RT for 15 min; at this point TLC showed that startingmaterial had been consumed. The solution was filtered, concentrated invacuo, and the residue was chromatographed (SiO₂; hex:EtOAc 4:1) toprovide the pure carbamate-ester (2 g). This was dissolved in a mixtureof THF (10 mL), MeOH (1 mL) and aqueous LiOH (8 mL of a 1 M solution).The solution was stirred at RT overnight, then acidified to pH 3 withexcess aqueous 1 M HCl. The solution was extracted with EtOAc (2×50 mL).The combined organic extracts were washed with H₂O (2×50 mL) and brine(50 mL), dried (Na₂SO₄), and concentrated in vacuo to provide titlecompound as a white solid (1.75 g; 63%). [M+H]⁺=501.2

[M+H]⁺=501.2; ¹H NMR (400 MHz; CDCl₃): δ 7.93-7.99 (m, 2H), 7.38-7.43(m, 3H), 7.23 (q, 1H, J=8 Hz), 7.02-7.12 (m, 3H), 6.98-7.02(m, 2H),6.82-6.89 (m, 2H), 4.71 (s, 1H), 4.64 (s, 1H), 4.25 (t, 2H, J=7 Hz),4.07 (s, 2H), 2.90-2.98 (m, 2H), 2.37 (s, 3H), 2.29 (s, 3H)

EXAMPLE 230

To a 0° C. solution of the secondary amine (3.0 g; 7.9 mmol)

in CH₂Cl₂ (45 mL) were successively added pyridine (0.8 mL; 9.9 mmol)and 4-methoxyphenyl chloroformate (1.3 mL; 8.7 mmol). The reaction wasstirred at 0° C. for 3 h, at which point starting material had beenconsumed (by analytical HPLC). The reaction solution was washed withaqueous HCl (2×25 mL of a 1 M solution), brine (2×), dried (Na₂SO₄), andconcentrated in vacuo. The crude product was chromatographed (SiO₂;stepwise gradient from 4:1 to 3:7 hex:EtOAc) to provide the desiredcarbamate-ester (4.2 g; 100%). The ester was dissolved in THF:MeOH:H₂O(50 mL of a 3:1:1 solution) and LiOH.H₂O (0.5 g; 11.9 mmol) was added.The solution was stirred overnight at RT. Starting material was stillpresent by HPLC. More LiOH.H₂O (0.2 g; 4.8 mmol) was added and themixture was briefly heated to solubilize the LiOH, then stirred at RTfor 4 h. The reaction was complete at this point, and the mixture wasacidified to pH 3 with excess aqueous 1 M HCl, then organic solventswere removed in vacuo. The residual aqueous phase was extracted withEtOAc (3×50 mL). The combined organic extracts were successively washedwith H₂O and brine (50 mL each), dried (Na₂SO₄), filtered andconcentrated in vacuo to give title compound as a colorless solid (3.07g; 75%).

[M+H]⁺=517.2; ¹H NMR (400 MHz; CDCl₃): δ 7.96-7.98 (m, 2H), 7.4-7.45 (m,3H), 7.2-7.3 (m, 2H), 7.0-7.1 (m, 2H), 6.8-7.0 (m, 4H), 4.65 (s, 1H),4.55 (s, 1H), 4.20-4.24 (m, 2H), 4.02 (s, 2H), 3.77 (s, 3H), 3.00 (s,2H), 2.38 (s, 3H).

The following examples (167, 187, 216, 229, 247 and 263) were allsynthesized according to the methods described for Examples 149 and 230.

EXAMPLE 167

¹H NMR (DMSO-d₆; 500 MHz): δ 2.37 (s, 3H), 2.94 (m, 2H), 3.73 (2s, 3H),4.06 (d, J=4.8 Hz, 2H), 4.25 (t, J=7.2 Hz, 2H), 4.66 (2s, 2H), 6.71 (m,3H), 6.85 (m, 2H), 7.06 (d, J=16 Hz, 1H), 7.22 (m, 2H), 7.39 (m, 3H),7.96 (m, 2H)

EXAMPLE 187

¹H NMR (DMSO-d₆; 500 MHz): δ 2.36 (s, 3H), 2.93 (t, J=6.6 Hz, 2H), 4.02(2s, 2H), 4.21 (t, J=6.6 Hz, 2H), 4.55 (2s, 2H), 6.94 (m, 3H), 7.48 (m,8H), 7.90 (m, 2H)

EXAMPLE 216

¹H NMR (CDCl₃; 400 MHz): δ 1.3-1.4 (m, 3H), 2.39 (s, 3H), 2.9-3.05 (m,2H), 3.9-4.05 (m, 2H), 4.06 (br s, 2H), 4.25 (t, J=7.0 Hz, 2H), 6.85(dd, J=11.4, 8.8 Hz, 2H), 6.99 (dd, J=15.8, 8.8 Hz, 2H), 7.18 (dd,J=8.4, 2.6 Hz, 2H), 7.38-7.50 (m, 5H), 7.99 (br d, J=7.9 Hz, 2H)

EXAMPLE 229

¹H NMR (CDCl₃; 400 MHz): δ 2.30 (2 peaks, 3H), 2.38 (2 peaks, 3H), 3.03(dd, J=5.7, 5.7 Hz; 2H), 3.99 (s, 2H), 4.21 (dd, J=6.1, 6.1 Hz; 2H),4.63 (2 peaks, 2H), 6.82-6.87 (m, 2H), 6.96-7.01 (m, 2H), 7.09-7.14 (m,2H), 7.18-7.20 (m, 2H), 7.43-7.45 (m, 3H), 7.96-7.98 (m, 2H)

EXAMPLE 247

¹H NMR (DMSO-D₆; 500 MHz): δ 2.36 (s, 3H), 2.93 (t, J=6.6 Hz, 2H), 3.74(s, 3H), 3.96 (2s, 2H), 4.20 (t, J=6.6 Hz, 2H), 4.55 (2s, 2H), 6.65 (m,2H), 6.94 (m, 3H), 7.27(m, 3H), 7.48 (m, 3H), 7.91 (d, J=6.1 Hz, 2H)

EXAMPLE 263

¹H NMR (CDCl₃; 400 MHz): δ 2.42 (2s, 3H; rotamers); 3.0-3.5 (m, 2H),3.99 (br s, 2H), 4.15-4.25 (m, 2H), 4.57 (AB doublet, J=38.2 Hz, 2H),6.85 (dd, J=11.4, 8.8 Hz, 2H), 6.99 (dd, J=15.8, 8.8 Hz, 2H), 7.18 (dd,J=8.4, 2.6 Hz, 2H), 7.38-7.50 (m, 5H), 7.99 (br d, J=7.9 Hz, 2H)

EXAMPLE 306

A solution of resorcinol monoacetate (2 g; 13.14 mmol),N,N-dimethylaniline (1.6 g; 13.14 mmol), phosgene (6.8 mL of a 1.95Msolution in toluene; 13.1 mmol) and a catalytic amount of DMF inchlorobenzene (5 mL) was heated at 80° C. in a pressure tube for 2.5 hand then allowed to cool to RT. The clear supernatant solution wasseparated and concentrated in vacuo. The residue was purified viadistillation in vacuo (140-150° C. @ 1.0 mm Hg) to give title compoundin the form of a clear oil (2 g; 71%).

To a mixture of Part A chloroformate (50 mg, 0.237 mmol) andpolyvinylpyridine (PVP) (75 mg, 0.70 mmol) was added a CH₂Cl₂ solution(2 mL) of the amino-tert-butyl ester (100 mg, 0.237 mmol),

(prepared as described in Example 7 Part B).

The reaction was stirred at RT for 15 min. Resin-bound amine (WA21J,Supelco; 150 mg) was added to the mixture. The reaction mixture wasstirred for another 15 min. The Resin-bound amine and PVP were removedvia filtration and the filtrate was concentrated in vacuo to give thecrude product. The crude product was chromatographed (SiO₂; hexane/EtOAc1:4) to provide title compound (0.1 g, 70%).

A solution of the Part B phenol-tert butyl ester compound (60 mg; 0.10mmol), Bu₄NBr (0.32 mg, 0.001 mmol), aqueous NaOH (0.5 mL of a 1 Msolution; 0.5 mmol) and isopropanol (1 mL) in a pressure tube was cooledto −50° C. Freon gas was bubbled into the solution for 1 min. The tubewas sealed and heated to 80° C. for 12 h. The mixture was extracted withEtOAc (3×10 mL). The combined organic extracts were washed with brine,dried (Na₂SO₄) and concentrated in vacuo to give the crudedifluoromethoxy ether-tert butyl ester as an oil. The crude ester wasthen treated with a solution of 30% TFA in CH₂Cl₂ overnight. Volatileswere removed in vacuo and the residue was purified using preparativereverse-phase HPLC (as in Example 127, except that the continuousgradient used was from A:B 70:30 to 100% B) to afford two products, thedesired title difluoromethoxy ether-acid (13 mg; 23%) and thephenol-acid set out below (32 mg; 63%). Reverse phase HPLC analysisusing standard conditions indicated that the product purity was >92%. Inaddition LC/MS (electrospray) gave the correct molecular ion[(M+H)⁺=553.2 and 503.2 respectively] for the two compounds.

EXAMPLES 307 and 308

Following the above general procedure of Example 306, the followingcompounds were prepared:

EXAMPLE 309

To a mixture of phenyl chlorothionoformate (11 mg, 0.063 mmol) andtriethylamine (6.5 mg, 0.063 mmol) was added a solution of theamino-tert-butyl ester (20 mg, 0.053 mmol),

(prepared as described in Example 7 Part B)in CH₂Cl₂ (1 mL). The reaction was stirred at RT for 15 min and themixture was concentrated in vacuo to give the crude thionocarbamatetert-butyl ester. This material was dissolved in aqueous LiOH (0.50 mLof a 1.0 M solution) and THF (2 mL) and stirred at RT for 5 h. Thesolution was concentrated in vacuo to give the crude acid as an oil. Thecrude product was purified using preparative HPLC to afford the desiredtitle product (10 mg; 38%). [M+H]⁺=503.2

EXAMPLE 310

The corresponding thiocarbamate in the 1,4 series was prepared in thesame manner as described for Example 309.

EXAMPLE 311

To a mixture of the amine-tert butyl ester (306 mg, 0.73 mmol)

(prepared as described in Example 7 Part B),and p-phenoxybenzoic acid (220 mg; 1.02 mmol; 1.4 equiv) in CH₃CN (20mL) was added BOP reagent (372 mg, 0.84 mmol, 1.15 equiv) in a singleportion followed by iPr₂NEt (0.5 mL; 2.9 mmol; 3.9 equiv) dropwise. Thereaction was stirred overnight at RT, after which volatiles were removedin vacuo. The residue was dissolved in EtOAc and washed with aqueous 1NHCl. The aqueous layer was extracted with EtOAc (2×) and the combinedorganic extracts were washed with H₂O, sat'd aqueous NaHCO₃ and brine,dried (Na₂SO₄) and concentrated in vacuo to give the desired product.The resulting crude amide-ester was used in the next step withoutfurther purification.

A solution of the crude amide ester in 40% TFA-CH₂Cl₂ (25 mL) wasstirred for 5 h at RT. Volatiles were removed in vacuo and the crudeacid was purified by Prep HPLC (YMC S5 ODS 30 mm×250 mm reverse phasecolumn; flow rate=25 mL/min; 30 min continuous gradient from 70:30 A:Bto 100% B; solvent A=90:10:0.1H₂O:MeOH:TFA; solvent B=90:10:0.1MeOH:H₂O:TFA) to yield title compound (238 mg; 58% yield over 2 steps)as a white solid. Analytical Reverse-phase HPLC: Retention time=7.53min. (Continuous gradient solvent system: from 50% A:50% B to 0% A:100%B (A=90% H₂O/10% MeOH/0.2% H₃PO₄; B=90% MeOH/10% H₂O/0.2% H₃PO₄) for 8min; detection at 220 nm; YMC S3 ODS 4.6×50 mm column). [M+H]⁺=563.3

EXAMPLE 311A

(Alternative Synthetic Procedure)

To a solution of the secondary amine tert-butyl ester (35 mg, 0.083mmol), (prepared as described in Example 7 Part B)

4-phenoxy benzoic acid (30 mg, 0.14 mmol) and HOAT (30 mg, 0.22 mmol) inTHF/DMF (1 mL/0.05 mL) was added EDCI (20 mg, 0.10 mmol) and the mixturewas stirred at RT overnight. The reaction was diluted with EtOAc, washedwith aqueous 1N HCl, H₂O, sat'd. aqueous NaHCO₃ and brine, dried(Na₂SO₄) and concentrated in vacuo. The crude amide-tert butyl ester wasdissolved in TFA/CH₂Cl₂ (5 mL of a 1:1 solution). The resulting pinksolution was stirred overnight and concentrated in vacuo to provide thecrude acid-amide as a dark brown oil. The crude product was purified bypreparative HPLC (YMC S5 ODS 20×100 mm column, 10 min continuousgradient from 60:40 A:B to 100% B; solvent A=90:10:0.1H₂O:MeOH:TFA;solvent B=90:10:0.1 MeOH:H₂O:TFA; flow rate=20 mL/min) to provide thetitle compound (32 mg, 69%). [M+H]⁺=563.3

EXAMPLE 312

-   1) To a solution of the secondary amine-tert-butyl ester (25 mg; 006    mmol)

(prepared as described in Example 7 Part B),in THF (0.5 mL) was added 2-naphthalene carboxylic acid (25 mg; 0.15mmol; 2.5 equiv).

-   2) HOAT (48 mg; 0.35 mmol; 5.8 equiv) was added.-   3) DMF (50 μL) was added.-   4) EDCI ((20 mg, 0.1 mmol, 1.8 m eq) was added.-   5) The reaction vessel was shaken for 24 h at RT.-   6) The reaction was diluted with MeOH (2 mL) and filtered.-   7) The amide-tert butyl ester was purified by preparative HPLC (YMC    S5 ODS 20×100 mm column; flow rate=25 mL/min; 10 min continuous    gradient from 70:30 A:B to 100% B; solvent A=90:10:0.1H₂O:MeOH:TFA;    solvent B=90:10:0.1 MeOH:H₂O:TFA).-   8) The fractions containing the purified amide-ester were treated    with a solution of TFA in CH₂Cl₂ (0.5 mL of a 1:1 solution)    overnight. The reaction was concentrated in vacuo (Speed Vac) to    give title compound (8 mg; 25%). Reverse-phase analytical HPLC    showed that the purity of the product was >88%; LC/MS (electrospray    detection) gave the correct [M+H]⁺=521.2 for the title compound.

EXAMPLE 313

A mixture of the amino-ester (20 mg; 0.0474 mmol),

(prepared as described in Example 7 Part B),thiophene-2-carboxylic acid (9.1 mg, 0.71 mmol), EDCI (26 mg, 1.4 mmol)and DMAP (a catalytic amount) was dissolved in CH₂Cl₂ (2 mL) and stirredat RT overnight. The reaction solution was successively washed withaqueous 1N HCl (2 mL) and sat'd aqueous NaHCO₃ (2 mL). To the organicphase was then added 0.5 g anhydrous Na₂SO₄, and 0.2 g WA21J amine-boundresin (Supelco). The mixture was shaken for 0.5 h and the solids werefiltered off. TFA (2.0 mL) was added to the filtrate and the solutionwas shaken at RT overnight. The reaction solution was concentrated invacuo using a Speed Vac for 16 h to afford title compound as a yellowoil. Reverse phase analytical HPLC (YMC S5 ODS 4.6×33 mm column,continuous gradient from 100% A to 100% B for 2 min at a flow rate of 5mL/min [Solvent A=10% MeOH/90% H₂O/0.2% H₃PO₄; Solvent B=90% MeOH/10%H₂O/0.2% H₃PO₄]) indicated that the product purity was 92.7%. Inaddition, LC/MS (electrospray) gave the correct molecular ion[(M+H)⁺=477.2] for the desired title compound.

EXAMPLE 314

Another purification protocol using amine-bound resin for the amide-acidproduct is illustrated by the following synthesis:

To a mixture of the amino-ester (20 mg; 0.0474 mmol),

(prepared as described in Example 7 Part B), and 3,5-dimethoxybenzoicacid (13 mg, 0.071 mmol) in anhydrous CH₃CN (0.5 mL) was added asolution of BOP reagent (31 mg, 0.071 mmol) in CH₃CN (0.5 mL), followedby DIEA (41 μL, 0.23 mmol) in CH₃CN (0.5 mL). The reaction was shaken atRT overnight. Volatiles were removed in vacuo using a Speed Vac andCH₂Cl₂ (2 mL) was added. The solution was washed successively withaqueous 1N HCl (2 mL) and sat'd aqueous NaHCO₃ (2 mL). To the organicphase was added 0.5 g anhydrous Na₂SO₄, and 0.2 g WA21J amine-boundresin (Supelco). The mixture was shaken for 0.5 h and the solids werefiltered. TFA (2 mL) was added to the filtrate and the solution wasshaken at RT overnight. The reaction solution was concentrated in vacuousing a Speed Vac for 16 h to afford the final product as a yellow gum.Reverse-phase analytical HPLC (YMC S5 ODS 4.6×33 mm column, continuousgradient from 100% A to 100% B for 2 min at a flow rate of 5 mL/min[Solvent A=10% MeOH/90% H₂O/0.2% H₃PO₄; Solvent B=90% MeOH/10% H₂O/0.2%H₃PO₄]) indicated that the product purity was 90%. In addition, LC/MS(electrospray) gave the correct molecular ion [(M+H)⁺=531.3] for thetitle compound.

EXAMPLES 315 to 391

Following one of the above procedures, the following compounds in Tables6 and 7 of the invention were prepared.

TABLE 6 (Amide-Acids)

Example No. R^(3e) [M + H]⁺ 315

521.2 316

507.3 317

563.1 318

561.2 319

499.3 320

559.2 321

491.1 322

522.2 323

491.2 324

543.3 325

515.3 326

535.3 327

499.3 328

485.3 329

503.3 330

517.3 331

513.3 332

527.3 333

519.3 334

515.3 335

515.3 336

529.3 337

477.2 338

471.2 339

501.3 340

489.2 341

539.2 342

529.3 343

515.3 344

485.3 345

501.3 346

505.2 347

505.2 348

527.3 349

539.2 350

489.3 351

523.2 352

515.3 353

511.2 354

523.1 355

499.2 356

503.2 357

521.2 358

529.2 359

529.2 360

530.2 361

530.2

TABLE 7 (Amide-Acids)

Example No. R³ [M + H]⁺ 362

499.2 363

547.2 364

563.2 365

561.1 366

595.1 367

593.1 368

595.1 369

597.1 370

563.1 371

547.2 372

563.1 373

577.2 374

561.2 375

561.2 376

536.2 377

577.2 378

577.2 379

615.3 380

499.3 381

519.3 382

507.3 383

539.2 384

505.2 385

505.2 386

522.7 387

513.3 388

527.3 389

529.3 390

527.3 391

523.1

EXAMPLE 392

To a solution of the amine (47 mg; 0.12 mmol)

(prepared as described in Example 3 Part A),in CH₂Cl₂ (5 mL) were added iPr₂NEt (0.1 mL; 0.57 mmol) and DMAP (14 mg;0.12 mmol) followed by benzyl isocyanate (24 mg; 0.18 mmol). Thereaction was stirred for 14 h, then passed through an SCX cartridge [the3 g SCX cartridge was prewashed successively with MeOH (10 mL) andCH₂Cl₂ (5 mL)] by eluting with CH₂Cl₂ (15 mL). The filtrate wasconcentrated in vacuo to give the crude urea Part A compound (53 mg;84%), which was sufficiently pure to be used in the next step withoutfurther purification.

A solution of the crude Part A urea-ethyl ester (53 mg) and LIOH.H₂O (12mg) in THF: MeOH:H₂O (3:1:1; 5 mL) was stirred at RT for 2 days. Thesolution was acidified to pH3 with aqueous 1M HCl, concentrated invacuo, and purified by preparative HPLC (utilizing a YMC S5 ODS 20mm×100 mm column; with a continuous gradient from 70% A:30% B to 100% Bfor 10 minutes at a flow rate of 20 mL/min, whereA=90:10:0.1H₂O:MeOH:TFA and where B=90:10:0.1 MeOH:H₂O:TFA) to givetitle compound (12 mg; 24%) as an off-white solid. [M+H]⁺=500.2

EXAMPLE 393

To a solution of the amine (0.25 g, 0.66 mmol)

(prepared as described in Example 6),in CH₂Cl₂ (5 mL) was added 4-methoxyphenyl isocyanate (0.20 g, 1.32mmol) in one portion and the resulting solution was stirred for 1 h atRT. The reaction mixture was then concentrated in vacuo to give an oil,which was chromatographed (SiO₂; 1.5% MeOH/CH₂Cl₂) to provide titlecompound (0.34 g; 97%) as a colorless oil.

A solution of Part A compound (0.14 g, 0.26 mmol) and LiOH (0.1 g, 4.3mmol) in H₂O/THF (5 ml of a 40:60 solution) was stirred for 12 h at 25°C. The reaction mixture was acidified with HOAc and extracted with EtOAc(2×). The combined organic extracts were dried (MgSO₄) and concentratedin vacuo to provide title compound (0.12 g; 90%) as a colorless oil.[M+H]⁺=516

¹H NMR (CD₃OD; δ): 7.94 (m, 2H), 7.45 (m, 3H), 7.23 (m, 3H), 6.80 (m,2H), 6.80 (m, 3H), 4.58 (s, 2H), 4.23 (t, J=7.9 Hz, 2H), 3.81 (s, 2H),3.73 (s, 3H), 2.98 (t, J=7.9 Hz, 2H), 2.36 (s, 3H).

EXAMPLE 394

A solution of the previously described carbamoyl chloride (Example 139Part A compound; 0.15 g; 0.34 mmol)

N-methyl-p-anisidine (0.14 g, 1.0 mmol) and K₂CO₃ (0.15 g, 1.1 mmol) in5 ml of acetone was stirred at 25° C. for 12 h. The reaction mixture wasconcentrated in vacuo to yield an oily residue, which waschromatographed (SiO₂; 1.5% MeOH/CH₂Cl₂) to provide title compound (0.12g; 65%) as a colorless oil.

A solution of Part A compound (0.12 g, 0.22 mmol) and LiOH (0.050 g, 2.1mmol) in H₂O/THF (5 mL of a 40:60 solution) was stirred at RT for 12 h.The reaction mixture was concentrated in vacuo to yield an oily residue,which was purified by preparative HPLC (YMC S5 ODS 30×250 mm column;flow rate=25 ml/min. 30 min continuous gradient from A:B=50:50 to 100%B; solvent A=90:10:0.1H₂O:MeOH:TFA; solvent B=90:10:0.1 MeOH:H₂O:TFA) toprovide title compound (59 mg, 50%) as a colorless oil. [M+H]⁺=530.3

NMR (CDCl₃): 7.99 (d, 6.2 Hz, 2H, 7.45 (m, 3H), 7.24 (m, 3H), 6.82 (d,6.2 Hz, 2H), 6.79 (m, 1H), 6.63 (m, 1H), 6.55 (s, 1H), 4.24 (s, 2H),4.16 (t, 7.8 Hz), 2H), 3.72 (s, 3H), 3.59 (s, 2H), 3.16 (s, 2H), 3.02(t, 7.8 Hz, 2H), 2.40 (s, 3H).

EXAMPLES 395 to 410

Utilizing one of the above procedures, the analogs in Tables 8 and 9were synthesized.

TABLE 8 (Urea-Acids)

Example No. R^(3f) [M + H]⁺ 395

562.3 396

546.3 397

554.2 398

532.3 399

522.3 400

546.3 401

516.3

TABLE 9 (Urea-Acids)

Example No. R^(3f) [M + H]⁺ 402

562.3 403

546.3 404

554.2 405

532.3 406

522.3 407

546.3 408

516.3 409

516.3

EXAMPLE 410

The title compound was prepared as part of a solution phase library runusing the following procedure:

To a mixture of 1-naphthylsulfonyl chloride (26.8 mg, 0.12 mmol) andDMAP (2 mg, 0.016 mmol) in pyridine (2 mL) was added a solution of theamino-t-butyl ester

(prepared as described in Example 8)(20 mg, 0.05 mmol) in pyridine (0.6 mL). The reaction was stirred at RTfor 20 h. Resin-bound amine (WA21J, Supelco; 5.8 mmol/g loading; 150 mg)was added to the mixture. The reaction was stirred for a further 4 h.The resin was filtered off and the filtrate was concentrated in vacuo togive the crude product, which was chromatographed (CUSIL12M6 column;United technology; 2 g of sorbent in a 6 mL column) by the procedureoutlined below.

-   1) The column was conditioned with hexane (20 mL).-   2) The residue was dissolved in a minimal volume of EtOAc and loaded    onto the silica gel column.-   3) The cartridge was eluted with Hex/EtOAc(3:1), Hex/EtOAc (1:1).    The desired fraction (identified by TLC) was collected and    concentrated to give title compound as a viscous oil which was used    in the next step without any further purification.

Et₃N ((0.3 ml of a 1M solution in CH₂Cl₂) and TMSI (0.3 ml of a 1Msolution in CH₂Cl₂) were successively added to a solution of Part Acompound in CH₂Cl₂. The reaction mixture was stirred at RT for 12 h andthen was concentrated in vacuo to give the crude product. The productwas purified by solid-phase extraction using a CHQAX12M6 column (Unitedtechnology; 2 g of sorbent in a 6 mL column) by the procedure outlinedbelow.

-   1) The column was conditioned with CH₂Cl₂ (25 mL).-   2) The residue was dissolved in a minimal volume of CH₂Cl₂ and    loaded onto the SAX column.-   3) The cartridge was washed successively with CH₂Cl₂ (25 mL),    CH₂Cl₂/MeOH (5% MeOH, 15 mL), CH₂Cl₂/MeOH (50% MeOH, 15 mL), MeOH    (20 mL).-   4) The product was eluted with a solution of 1% TFA in MeOH (20 mL).

The final product-containing fraction was collected and concentrated invacuo using a Speed Vac to afford BMS-329075 (16 mg; 62%). Reverse-phaseanalytical HPLC indicated that the product purity was 90%. In addition,LC/MS (electrospray) gave the correct molecular ion [(M+H)⁺=557.1] forthe desired compound.

EXAMPLE 411

(X=halogen, alkyl, CF₃, CF₃O, etc.)

The following general procedure was utilized for the preparation of therequisite substituted benzyl sulfonyl chlorides:

Cl₂ gas was bubbled into a 0° C. solution of 4-fluorobenzyl mercaptan(1.0 g, Lancaster) in glacial acetic acid (100 mL) and H₂O (5.0 mL) for1 h. The reaction mixture was then poured into ice-H₂O and immediatelyextracted with CH₂Cl₂ (200 mL); the organic phase was cautiously washedsuccessively with H₂O (200 mL), aqueous saturated NaHCO₃ (2×100 mL), andfinally brine (200 mL). The organic phase was dried (MgSO₄) andconcentrated in vacuo to furnish 4-fluorobenzyl sulfonyl chloride as acolorless solid (1.3 g; 89%).

To a solution of the secondary amine methyl ester (25 mg; 0.066 mmol)

(prepared as described in Example 6),in pyridine (0.8 mL) was added 4-fluorobenzyl sulfonyl chloride (68 mg;0.33 mmol; 5 equiv). The mixture was heated to 75° C., stirred overnightat 75° C., and then concentrated in vacuo. The black residue was treatedwith aqueous LiOH (1.0 mL of a 0.3 M solution) in H₂O/MeOH/THF for 18 h,then concentrated in vacuo. The residue was acidified with 1.0 M aqueousHCl to pH=1-2 and extracted with EtOAc (2×), dried (Na₂SO₄) andconcentrated in vacuo to give the crude product. Purification bypreparative HPLC (YMC S5 ODS 20 mm×250 mm reverse-phase column; 15 mincontinuous gradient from 60:40 A:B to 100% B with 10 min hold time,where A=90:10:0.1H₂O:MeOH:TFA and B=90:10:0.1 MeOH:H₂O:TFA; flow rate=25mL/min) gave the title compound (12 mg; 34%) as a white solid.[M+H]⁺(LC/MS)=539.1

EXAMPLES 412 to 456

Utilizing one of the above procedures, the analogs in Tables 10 and 11were synthesized.

TABLE 10 (Sulfonamide-Acids)

Example No. R^(3g) [M + H]⁺ 412

507.3 413

575.2 414

525.2 415

521.2 416

533.2 417

513.2 418

535.3 419

575.2 420

581.1 421

590.3 422

589.2 423

535.3 424

539.1 425

541.2 426

589.0 427

573.2 428

555.2 429

555.3 430

589.2 431

535.3 432

605.3 433

577.4

TABLE 11 (Sulfonamide-Acids)

Example No. R^(3g) [M + H]⁺ 434

549.4 435

557.3 436

506.3 437

549.3 438

541.2 439

521.3 440

533.3 441

535.4 442

575.3 443

678.3 444

597.4 445

589.2 446

535.3 447

539.1 448

539.1 449

589.0 450

573.2 451

555.2 452

555.3 453

589.2 454

535.3 455

605.3 456

577.4

EXAMPLE 457

To a 0° C. solution of methyl 2-hydroxypyridine-5-carboxylate (0.2 g,1.3 mmol), 2-(5-methyl-2-phenyl oxazol-4-yl)ethanol (0.32 g, 1.56 mmol)and Ph₃P (0.38 g, 1.56 mmol) in CH₂Cl₂ (10 mL) was added DEAD (0.2 mL,1.95 mmol) dropwise and the reaction was stirred at 25° C. for 12 h. Thesolution was concentrated in vacuo, and chromatographed on SiO₂ (4:1hex:EtOAc) to provide title compound (0.28 g, 63%) as an oil.

To a −78° C. solution of Part A compound (0.28 g., 0.82 mmol) in THF (10mL) was added DIBALH (2.0 mL of a 1 M solution in CH₂Cl₂; 1.95 mmol) andthe reaction was stirred at −78° C. for 4 h. TLC of an aliquot of thereaction showed the presence of both the corresponding aldehyde andalcohol. The reaction was warmed to 25° C. and stirred at RT for 1 h,after which only the alcohol was observed by TLC. The reaction wasquenched with water and diluted with EtOAc. The organic layer was washedwith brine, dried (MgSO₄), and concentrated in vacuo to furnish titlecompound as an oil. This crude material was used in the next reactionwithout further purification.

To a −78° C. solution of oxalyl chloride (0.22 mL, 2.6 mmol) and DMSO(0.37 mL, 5.2 mmol) in CH₂Cl₂ (15 mL) was added dropwise a solution ofPart B compound (0.42 g of crude material in 5 mL CH₂Cl₂). The reactionmixture was stirred for 2 h at −78° C. and then Et₃N (1 mL) was addeddropwise. The reaction mixture was stirred for an additional 0.5 h at−78° C. and then was slowly warmed to 25° C. The reaction mixture wasdiluted with EtOAc (200 mL) and washed successively with aqueous NaHCO₃and brine. The organic layer was dried (MgSO₄), then concentrated invacuo to provide title compound (0.40 g; 95%) as an oil, which was usedin the next step without further purification.

A mixture of Part C compound (<0.82 mmol), glycine methyl esterhydrochloride (0.5 g., 4.0 mmol), NaBH(OAc)₃ (0.85 g., 4.0 mmol) and DCE(10 mL) was stirred at 25° C. for 12 h. The reaction mixture was thendiluted with EtOAc (50 mL) and washed successively with aqueous NaHCO₃and brine. The organic layer was dried (MgSO₄), then concentrated invacuo to give title compound (0.31 g; 82%) as an oil (>95% pure byanalytical reverse-phase HPLC) which was used in the next step withoutfurther purification.

A mixture of Part D compound (0.050 g; 0.13 mmol), 4-phenoxybenzaldehyde(0.048 g; 0.26 mmol), NaBH(OAc)₃ (0.082 g; 0.39 mmol) in DCE (10 mL) wasstirred at 25° C. for 12 h. The reaction mixture was diluted with EtOAc(50 mL) and washed successively with aqueous NaHCO₃ and brine. Theorganic layer was dried (MgSO₄), then concentrated in vacuo to give thetertiary amino methyl ester as an oily residue. To this residue, LiOH(0.050 g) and H₂O/THF (2 mL of a 60/40 solution) were added and thereaction was stirred at RT for 12 h. Preparative HPLC (YMC S5 ODS 30×250mm column−continuous gradient over 30 min; flow rate=25 mL/min from30:70 A:B to 100% B; A=90:10:0.1H₂O:MeOH:CF₃CO₂H; B=90:10:0.1MeOH:H₂O:CF₃CO₂H) provided title compound (0.021 g; 30%) as a TFA salt.

¹H NMR (CDCl₃) δ: 8.18 (s, 1H), 7.94 (d, 6.6 Hz, 2H), 7.86 (d, 8.8 Hz,1H), 7.45 (m, 3H), 7.34 (m, 3H), 7.14 (t, 7.4 Hz, 1H), 7.02-6.92 (m,5H), 6.81 (t, 8.8 Hz, 1H), 4.51 (m, 6H), 3.59 (s, 2H), 3.06 (t, 6.2 Hz,2H)

EXAMPLE 458

A mixture of 2-hydroxypyridine-6-carboxylic acid (1.30 g, 9.4 mmol),concentrated H₂SO₄ (0.5 mL) and MeOH (20 mL) was heated to reflux for 12h. The reaction was complete at this point by analytical HPLC. Thereaction mixture was concentrated in vacuo to give a light yellow oil,which was diluted with EtOAc and washed with aqueous NaHCO₃. The organicphase was dried (MgSO₄) and concentrated in vacuo to yield titlecompound as a solid (0.43 g, 30%).

To a solution of Part A compound (0.43 g, 2.8 mmol),2-(5-methyl-2-phenyloxazol-4-yl)ethanol (0.68 g, 3.3 mmol) and Ph₃P (1.0g, 4.07 mmol) in THF (10 mL) was added DEAD (0.66 mL, 4.2 mmol) and thereaction was stirred at RT for 12 h. The solution was concentrated invacuo and the residue was chromatographed (SiO₂; 20% acetone/hexanes) toprovide title compound as an oil (0.92 g; 97%).

To a solution of Part B compound (0.92 g, 2.7 mmol) in THF (50 mL) wasadded LiAlH₄ (5 mL of a 1.0 M solution in THF, 5 mmol) dropwise at −78°C. and the resulting reaction was allowed to warm to 0° C. over 2 h. Thereaction was then quenched by adding a few pieces of ice into themixture. The reaction mixture was partitioned between EtOAc (200 mL) andbrine (50 mL). The organic phase was dried (MgSO₄) and concentrated invacuo to give an oil (0.92 g; 95%) which was used in the next reactionwithout further purification.

To a solution of oxalyl chloride (0.47 mL, 5.4 mmol) and DMSO (0.36 mL,10.8 mmol) in CH₂Cl₂ (15 mL) was added dropwise a solution of Part Ccompound (0.92 g; >2.7 mmol) in CH₂Cl₂ (10 mL) at −78° C. The reactionmixture was stirred for 2 h and then Et₃N (1 mL) was added dropwise. Thereaction mixture was allowed to stir for an additional 0.5 h at −78° C.and then slowly warmed to 25° C. The reaction mixture was then dilutedwith EtOAc (200 mL) and washed successively with aqueous NaHCO₃ andbrine. The organic layer was dried (MgSO₄) and then concentrated invacuo to yield title compound (0.90 g; >90% pure by ¹H NMR analysis) asan oil. This material was used in the next step without furtherpurification.

To a solution of Part D compound (0.90 g; 2.7 mmol), glycine methylester hydrochloride (1.7 g, 13.5 mmol) in 1,2 dichloroethane (10 mL) wasadded NaBH(OAc)₃ (1.7 g, 8.1 mmol) in one portion. The resultingsolution was stirred at 25° C. for 12 h. The reaction mixture wasconcentrated in vacuo to give an oil, which was chromatographed (SiO₂;30% acetone in hexane) to provide title compound (0.86 g; 83%) as acolorless oil.

A solution of Part E compound (0.040 g, 0.1 mmol), 4-phenoxybenzaldehyde(0.030 g, 0.15 mmol) and NaBH(OAc)₃ (0.060 g, 0.3 mmol) in DCE (10 mL)was stirred at RT for 12 h. The reaction mixture was concentrated invacuo and the oily residue was chromatographed (SiO₂; 30% acetone inhexane) to provide the amino-ester title compound (56 mg; >95%) as acolorless oil.

A solution of Part F compound (56 mg; 0.1 mmol) and LiOH (0.050 g; 0.21mmol) in H₂O/THF (2 mL of a 6:4 solution) was stirred at RT for 12 h.The reaction mixture was concentrated in vacuo to give a white solid,which was dissolved in MeOH and purified by preparative HPLC (YMC S5 ODS30×250 mm column; continuous gradient over 30 min; flow rate=25 mL/minfrom 30:70 A:B to 100% B; A=90:10:0.1H₂O:MeOH:TFA; B=90:10:0.1MeOH:H₂O:TFA). Title compound (41 mg; 72%) was obtained as a TFA salt.

¹H NMR (MeOH-D₄): 7.90 (m, 2H), 7.71 (t, 8.4 Hz, 1H), 7.51 (d, 8.7 Hz,2H), 7.44 (m, 3H), 7.36 (t, 8.7 Hz, 2H), 7.17 (t, 8.4 Hz, 1H), 6.96 (m,5H), 6.82 (d, 8.4 Hz, 1H), 4.62 (t, 6.2 Hz, 2H), 4.56 (s, 2H), 4.50 (s,2H), 4.17 (s, 2H), 3.00 (t, 6.2 Hz, 2H), 2.36 (s, 3H). C₃₄H₃₁N₃O₅=550.23(M+H⁺) by LC/MS (electrospray).

EXAMPLE 459

To a 0° C. solution of 2-(5-methyl-2-phenyloxazol-4-yl)ethanol (1.07 g,5.25 mmol), Ph₃P (1.38 g, 5.25 mmol) and N-Boc-4-hydroxyphenylethylamine(1.24 g, 5.25 mmol) in THF (36 mL) was added DEAD (0.83 mL, 5.25 mmol).The reaction was allowed to warm to RT and stirred for 15 h. Thereaction mixture was concentrated in vacuo, and the residue waschromatographed (SiO₂; stepwise gradient from 95:5 to 4:1 hex:EtOAc) toobtain title compound (1.43 g, 65%).

A solution of Part A compound (1.01 g, 2.37 mmol) and TFA (8 mL) inCH₂Cl₂ (30 mL) was stirred at RT for 4.5 h. The solution wasconcentrated in vacuo, and the residue was dissolved in CH₂Cl₂ andfiltered through a pad of solid K₂CO₃. The filtrate was concentrated invacuo to give the corresponding crude amine. To a solution of the crudeamine in THF (11.9 mL) were added pyridine (0.383 mL, 4.74 mmol) and2,4-dinitrobenzenesulfonyl chloride (0.85 g, 3.19 mmol) and the solutionwas stirred at RT for 15 h. Since some starting material still remainedat this point, more sulfonyl chloride (0.32 g, 1.2 mmol) was then added.After a further 4 h, HPLC analysis indicated that all starting materialhad been consumed. The reaction mixture was diluted with Et₂O, washedwith 1N aq HCl, saturated aq NaHCO₃ and brine, dried (MgSO₄), filteredand concentrated in vacuo to provide the crude2,4-dinitrobenzenesulfonamide

To a solution of the crude 2,4-dinitrobenzene-sulfonamide in CH₃CN (3mL) were added K₂CO₃ (excess) and tert-butyl bromoacetate (7.11 mmol).The reaction was stirred at RT overnight. HPLC analysis indicated theratio of product to starting material was 2/1. More DMF (3 mL), K₂CO₃and tert-butyl bromoacetate were added to the reaction mixture. Thereaction was complete in 2 h. The reaction mixture was diluted withEt₂O, washed with 1N aq HCl, saturated NaHCO₃ and brine, dried (MgSO₄),and concentrated in vacuo to provide the crude tert-butyl ester. Thiscrude material was chromatographed (SiO₂; hexanes/EtOAc; stepwisegradient from 9:1 to 2:1) to give title compound (0.663 g, 42% overall).

To a solution of Part B compound (0.663 g, 0.995 mmol) in THF (2.5 mL)were added Et₃N (0.208 mL, 1.49 mmol) and mercaptoacetic acid (0.090 mL,1.29 mmol). The reaction was stirred at RT overnight. The reactionmixture was then diluted with Et₂O, washed with 1N aq HCl, saturatedNaHCO₃ and brine, dried (MgSO₄), and concentrated in vacuo. The residuewas chromatographed (SiO₂; hexanes/EtOAc; stepwise gradient from 9:1 to2:1) to give title compound (0.265 g, 61%).

To a solution of Part C compound (0.015 g, 0.0344 mmol) in DCE (1 mL)were added 4-phenoxybenzaldehyde (0.103 mmol) and NaBH(OAc)₃ (0.0365 g,0.172 mmol). The reaction was stirred at RT for 15 h. The reactionmixture was filtered through a cotton plug to provide a clear solution,which was diluted with CH₂Cl₂, washed with saturated aq NaHCO₃ andbrine, dried (MgSO₄), and concentrated in vacuo. The crude product waspurified by preparative HPLC (YMC S5 ODS 30×250 mm column: flow rate 25mL/min, gradient 20% B to 100% B over 25 min, 100% B hold for 15 min,Retention time=29.1 min) to furnish the tert-butyl ester. A solution ofthis material was dissolved in CH₂Cl₂ (1.3 mL) and TFA (0.5 mL) wasadded slowly. The reaction was stirred at RT overnight and was thenconcentrated in vacuo. The residue was then dissolved in CH₂Cl₂, washedwith H₂O, saturated aq NaHCO₃ and brine, dried (MgSO₄) and concentratedin vacuo to give title compound (0.012 g, 61%). LC/MS gave the correct[M+H]⁺=563.3

Further analogs (as shown in the table below) were synthesized by thesame reductive amination procedure as described in Example 459 Part Dusing Example 459 Part C compound and different aromatic aldehydes. Inaddition carbamate-acids such as Example 461 compound were alsosynthesized using the general method described previously for thesynthesis of the Example 136 compound.

TABLE 12

Example No. R³ [M + H]⁺ 460

571.3 461

515.3 462

471.3

EXAMPLE 463

To a solution of the Example 230 acid (240 mg, 0.47 mmol) in DMF (2.0mL) were added HOAT (68 mg, 0.49 mmol), EDAC (94 g, 0.49 mmol) and2-cyanoethylamine (34 mg, 0.49 mmol). The solution was stirred at RT for18 h; analysis of the reaction by LC-MS showed that starting materialwas still present. Additional 2-cyanoethylamine (34 mg, 0.49 mmol) wasadded and the reaction mixture was stirred at RT for 48 h. Volatileswere removed in vacuo and the residue was dissolved in CH₂Cl₂ (40 mL)and washed successively with water (2×30 mL) and brine (30 mL). Theorganic phase was dried (MgSO₄) and concentrated in vacuo. The resultingwhite residue was dissolved in a minimum amount of CH₂Cl₂ (3 mL) andprecipitation by the cautious addition of EtOAc furnished the amideproduct title compound (184 mg; 70%) as a white solid.

To a 0° C. solution of Part A compound (180 mg; 0.32 mmol) in CH₂Cl₂(1.5 mL) were successively added Ph₃P (83 mg; 0.32 mmol), DEAD (100 μL,0.64 mmol) and TMSN₃ (85 uL, 0.64 mmol). The reaction mixture wasstirred at RT for 24 h. LC-MS analysis showed that a significant amountof starting material still remained. The reaction mixture was thenconcentrated in vacuo to ⅔ of the original volume and additional Ph₃P,DEAD and TMSN₃ (1 equivalent of each reagent) were added. The reactionmixture was stirred at RT for another 24 h and then diluted with EtOAc(40 mL). The solution was treated with 5% aqueous CAN solution (10 mL)and stirred for 15 min. The reaction solution was washed with water (30mL) and brine (30 mL), dried (MgSO₄) and concentrated in vacuo. Theresidue was chromatographed (SiO₂; ether:CH₂Cl₂ 3:7) to furnish thetitle compound (100 mg; 53%) as a white solid.

To a solution of Part B compound (100 mg, 0.17 mmol) in THF/1,4-dioxane(6:1, 1.4 mL) was added aqueous NaOH solution (0.6 mL of a 1.0 Msolution, 3.5 equiv). The mixture was stirred at RT for 14 h and thenacidified to ˜pH 2 with 1.0 M aqueous H₃PO₄ solution. EtOAc (30 mL) wasadded, and the organic phase was washed with water (15 mL) and brine (15mL), dried (MgSO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; 4% MeOH/CH₂Cl₂) to give the title tetrazole (35mg; 38%) as a white foam. LC/MS (electrospray) gave the correctmolecular ion: [M+H]⁺=541.3

EXAMPLE 464

A mixture of 2-hydroxybenzaldehyde (500 mg, 4.09 mmol), glycine methylester hydrochloride (544 mg, 4.09 mmol) and Et₃N (495 mg, 4.9 mmol) indry MeOH (5 mL) was stirred at RT for 3 h. NaBH₄ (155 mg, 4.09 mmol) wasthen added in three portions. The reaction was stirred at RT for another30 min. Saturated aqueous Na₂CO₃ (1 mL) was added to destroy theremaining NaBH₄ and then aqueous HCl (10 mL of a 1N solution) was added.The aqueous phase was washed with EtOAc (3×20 mL), then carefullybasified with 1N aq NaOH to pH=7-8. The aqueous phase was then extractedwith EtOAc (3×20 mL). The orange-red solution was concentrated in vacuoto give title compound as a yellow viscous oil.

Part A compound (38 mg, 0.195 mmol), 4-methoxyphenyl chloroformate andpyridine (39 mg, 5 mmol) was dissolved in 0.1 mL CH₂Cl₂, for 5 min. Thereaction mixture was then washed with aqueous HCl (2×2 mL of a 1Nsolution). The organic phase was washed with brine, dried (Na₂SO₄),concentrated in vacuo and chromatographed (SiO₂; hex:EtOAc=7:3) to givetitle compound (40 mg; 59%) as a pale yellow oil.

To a solution of Part B compound (40 mg, 0.116 mmol),2-[2-phenyl-5-methyl-oxazole-4-yl]-ethanol (Maybridge; 24 mg, 0.116mmol) and Ph₃P (40 mg, 0.151 mmol) in dry THF (3 mL) was added dropwiseDEAD (26 mg, 0.151 mmol). The solution was stirred at RT overnight. Theorange-red solution was concentrated in vacuo and the residue waspurified by Prep-HPLC (continuous gradient from 50% A:50% B to 100% B;A=90% H₂O:10% MeOH+0.1% TFA); (B=90% MeOH/10% H₂O+0.1% TFA) for 10 min;YMC SH-343-5 ODS 20×100 mm (5 μm) column) to provide title compound (30mg, 47%) as a yellow viscous oil.

Part C compound was dissolved in MeOH (3 mL) and H₂O (0.3 mL). To thissolution was added LiOH (3 mg) and the reaction was stirred at RT for 3h. Volatiles were removed in vacuo and the solution was acidified with1N aqueous HCl to pH=˜3-4. The aqueous phase was extracted with EtOAc(3×10 mL). The combined organic extracts were washed with brine, dried(Na₂SO₄) and concentrated in vacuo to give title compound as a whitesolid (18 mg; 64%). LC/MS (electrospray) gave the correct molecular ion[(M+H)⁺=516].

¹H NMR (δ): 2.27-2.32 (m, 3H), 2.96-2.98 (m, 2H), 3.65-3.69 (d, 3H),4.06-4.20 (m, 4H), 4.55-4.63 (d, 2H), 6.74-6.93 (m, 4H), 7.19-7.35(m, 2h), 7.88-7.90 (m, 2H).

EXAMPLE 465

A mixture of β-alanine methyl ester hydrochloride (51 mg; 0.363 mmol),Et₃N (50 μL; 0.363 mmol) and the aldehyde (100 mg; 0.33 mmol)

in MeOH (1 mL) was stirred at RT for 3 h. NaBH₄ (14 mg; 0.363 mmol) wasthen added and the reaction was stirred at RT for another 1 h. Volatileswere removed in vacuo and the residue was partitioned between saturatedaqueous Na₂CO₃ and EtOAc (20 mL each). The organic phase wasconcentrated in vacuo to give Part A compound as a yellow oil which wasused in the next step without further purification.

To a solution of Part A compound (20 mg; 0.050 mmol) and pyridine (0.50mL) in CH₂Cl₂ (2 mL) was added 3-chlorophenyl chloroformate (14 mg;0.070 mmol). The reaction was stirred at RT for 2 h, then volatiles wereremoved in vacuo. The residue was purified by preparative HPLC (YMC S5ODS 20×75 mm reverse phase column; continuous gradient from 50:50 A:B to100% B, where A=90:10:0.1H₂O:MeOH:TFA and B=90:10:0.1 MeOH:H₂O:TFA) togive Part B compound.

A solution of Part B compound and LiOH.H₂O (5 mg) in THF:H₂O (4:1) wasstirred at RT for 1 h. The reaction solution was acidified to pH 3 withaqueous HCl, then extracted with EtOAc. The combined organic extractswere concentrated in vacuo to give title compound (5 mg; 18%) as a whitesolid. [M+H]⁺=535.2; 537.2

EXAMPLE 466

Title compound was synthesized using the same sequence as in Example 465with the exception that the aldehyde

was used. [M+H]⁺=535.2; 537.2

Following procedures as described above, Examples 467 to 472 compoundswere prepared.

EXAMPLES 467 TO 469

Example No. R³ [M + H]⁺ 467

501.3 468

563.3 469

515.3

EXAMPLES 470 TO 472

Example No. R³ [M + H]⁺ 470

501.3 471

563.3 472

515.3

EXAMPLE 473

A mixture of 3-iodophenol (2.0 g; 9.1 mmol), acetic anhydride (4.6 g;45.5 mmol) and pyridine (3.6 g; 45.5 mmol) was stirred in CH₂Cl₂ (20 mL)for 3 h. The resulting mixture was washed with saturated aqueous NH₄Cl(3×100 mL), dried (MgSO₄) and concentrated in vacuo to give Part Acompound (2.30 g; 97%) as a yellow oil.

A mixture of Part A compound (1.00 g; 4.0 mmol), trimethylsilylacetylene(780 mg; 8 mmol), CuI (15 mg; 0.08 mmol) and (Ph₃P)₂Pd₂Cl₂ (28 mg; 0.04mmol) in diethylamine (10 mL) was stirred at RT for 3 h. Volatiles wereremoved in vacuo and the residue was chromatographed (SiO₂; hexane:EtOAc4:1) to give crude Part B compound, which was used in the next stepwithout further purification.

To a solution of crude Part B compound in CH₂Cl₂ (2 mL) were addedpyridine (3 mL; 37 mmol)) and acetic anhydride (4 mL; 42 mmol). Thereaction was stirred at RT for 2 h, then was partitioned betweensaturated aqueous NH₄Cl (30 mL) and CH₂Cl₂. The organic phase was washedwith additional saturated aqueous NH₄Cl (30 mL) and H₂O (100 mL), dried(Na₂SO₄) and concentrated in vacuo to give Part C compound, which wasused in the next step without further purification.

A solution of crude Part C compound and Bu₄NF (1.1 g; 12 mmol) in THF(10 mL) was stirred at RT for 1.7 h, after which all starting materialhad been consumed. The reaction solution was washed with H₂O, Celite®was added, and volatiles were removed in vacuo. The solids werechromatographed (SiO₂; hexane:EtOAc 9:1) to give Part D compound (400mg; 63% over 3 steps).

A mixture of Part D compound (400 mg; 2.5 mmol) and Pd/CaCo₃/Pb catalyst(40 mg; Aldrich) in MeOH (20 mL) was stirred under an atmosphere of H₂for 30 min. The mixture was filtered through Celite and the filtrate wasconcentrated in vacuo. The residue was chromatographed (SiO₂;hexane:EtOAc 95:5) to give Part E compound (310 mg; 77%) as a colorlessoil.

To a 0° C. solution of Part E compound (310 mg; 1.9 mmol) in DCE (10 mL)were successively added dropwise neat diethylzinc (491 μL; 4.8 mmol;Aldrich) and ICH₂Cl (700 μL; 9.6 mmol). The reaction mixture was allowedto warm to RT and then stirred at RT for 3 h, after which it waspartitioned between saturated aqueous NH₄Cl and EtOAc (50 mL each). Theorganic phase was washed with saturated aqueous NH₄C₁ and H₂O (50 mLeach) and concentrated in vacuo. The residue was chromatographed (SiO₂;hexane:EtOAc 9:1) to furnish Part F compound (230 mg; 69%) as acolorless oil.

A mixture of Part F compound (100 mg; 0.57 mmol) and K₂CO₃ (157 mg; 1.1mmol) in MeOH (5 mL) was stirred at RT overnight (no reaction). AqueousLiOH (1.1 mL of a 1 M solution; 1.1 mmol) was added and the solution wasstirred at RT overnight. Volatiles were removed in vacuo and the residuewas partitioned between aqueous 1 M HCl and EtOAc. The organic phase wasconcentrated in vacuo and the residue was chromatographed (SiO₂;hexane:EtOAc 4:1) to furnish Part G compound (70 mg; 92%) as a yellowoil.

To a solution of Part G compound (6 mg; 0.045 mmol) in DMF (0.2 mL) wasadded potassium t-butoxide (5 mg; 0.05 mmol). The reaction was stirredfor 2 min at RT, after which the carbamoyl chloride (20 mg; 0.045 mmol)

was added and the reaction was stirred at RT for a further 15 min.Volatiles were then removed in vacuo and the residue was chromatographed(SiO₂; hexane:EtOAc 7:3) to furnish Part H compound (11 mg; 45%) as ayellow oil.

A solution of Part H compound and LiOH.H₂O in MeOH/H₂O (10 mL of a 9:1mixture) was stirred at RT overnight. The solution was then acidified topH ˜3 with aqueous HCl and extracted with EtOAc. The combined organicextracts were concentrated in vacuo and purified by preparative HPLC togive title compound (10.1 mg; 95%) as an off-white lyophilate.[M+H]⁺=527.3

EXAMPLE 474

A mixture of 3-benzyloxybenzaldehyde (2.00 g; 1.0 mmol), ethylbromoacetate (1.67 g; 1.0 mmol) and Cs₂CO₃ (3.25 g; 1.0 mmol) in DMF (20mL) was stirred at RT for 8 h. The reaction mixture was partitionedbetween H₂O (300 mL) and EtOAc (100 mL). The aqueous phase was extractedwith EtOAc (2×100 mL). The combined organic extracts were washed withbrine, dried (Na₂SO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; 85:15 hex:EtOAc) to obtain Part A compound (3.48g; >100%) as a colorless oil.

To a solution of Part A compound (3.4 g; 11.9 mmol) in dry THF (50 mL)under Ar was added LiAlH₄ (36 mL of a 0.5 M solution in THF; 17.8 mmol)dropwise. The reaction was stirred at RT for 1 h. The reaction wasquenched by slow addition of saturated aqueous NH₄Cl (1 mL). Volatileswere removed in vacuo and the residue was partitioned between EtOAc (100mL) and 1 M aqueous HCl. The organic phase was dried (Na₂SO₄) andconcentrated in vacuo to give Part B compound (2.4 g; 98%) as a whitesolid.

To a solution of Part B compound (2.4 g; 9.8 mmol) and Ph₃P (3.1 g; 14.7mmol) in CH₂Cl₂ was added CBr₄ (4.80 g; 14.7 mmol). The reaction wasstirred at RT overnight, then concentrated in vacuo. The residue waschromatographed (SiO₂; 95:5 hex:EtOAc) to give Part C compound (2.8 g;93%) as a white solid.

A mixture of Part C compound (310 mg; 1.0 mmol) and potassiumtert-butoxide (113 mg; 2.0 mmol) in toluene (20 mL) was heated at 105°C. for 20 min. Additional KOtBu (56 mg; 1.0 mmol) was added and thereaction heated at 105° C. for another 10 min. The mixture was cooled toRT and partitioned between H₂O (100 mL) and EtOAc (100 mL). The organicphase was washed with H₂O (2×100 mL), dried (Na₂SO₄) and concentrated invacuo. The reaction was repeated with additional Part C compound (500mg; 1.63 mmol) and KOtBu (182 mg; 16 mmol). The combined crude reactionproducts were chromatographed (SiO₂; hexane) to give Part D compound(590 mg; 89%) as a colorless oil.

To a 0° C. solution of Part D compound (1.4 g; 62 mmol) in DCE (100 mL)was added neat diethylzinc (1.6 mL; 16 mmol) dropwise, followed byICH₂Cl (5.46 g; 31 mmol). The reaction mixture was allowed to warm to RTand stirred at RT overnight, then washed with 1M aqueous HCl. Theorganic phase was dried (Na₂SO₄) and concentrated in vacuo. The cruderesidue was chromatographed twice (SiO₂; hexane) to give Part E compound(510 mg; 30%) in addition to recovered starting material Part D compound(250 mg; 18%).

To a −78° C. solution of Part E compound (510 mg; 2.2 mmol) in liquidNH₃ (30 mL) was added Na (500 mg; 22 mmol). The dark blue solution wasstirred at −78° C. for 4 h, then was allowed to warm to RT overnight.The remaining solid residue was partitioned between 1 M aqueous HCl andEtOAc (50 mL each). The organic phase was dried (Na₂SO₄) andconcentrated in vacuo. The crude product was chromatographed (SiO₂; 9:1hexane:EtOAc) to give Part F compound (240 mg; 75%) as a yellow oil.

To a solution of Part F compound (150 mg; 1.0 mmol) in DMF (10 mL) weresuccessively added KOtBu (112 mg; 1.0 mmol) and a solution of thefollowing carbamoyl chloride (44 mg; 1.0 mmol) in DMF (0.5 mL).

(prepared as described in Examples 5 and 139). The reaction was stirredat RT for 15 min, after which analytical HPLC indicated that allstarting material had been consumed. The mixture was partitioned betweenH₂O and EtOAc (100 mL each). The organic phase was washed with H₂O(2×100 mL), dried (Na₂SO₄) and concentrated in vacuo. The crude productwas chromatographed (SiO₂; 9:1 hexane:EtOAc) to give impure Part Gcompound as a yellow oil.

A solution of Part G compound (556 mg; 1.0 mmol) and LiOH. H₂O (116 mg;2.8 mmol) in 10:1 MeOH:H₂O (10 mL) was stirred at RT for 2 h. Volatileswere removed in vacuo and the residue was acidified to pH 2 with aqueous1 M HCl, then extracted with EtOAc (3×40 mL). The combined organicextracts were dried (Na₂SO₄) and concentrated in vacuo. The crudeproduct was purified by preparative HPLC (YMC S5 ODS 50×250 mm column;flow rate=25 mL/min; continuous 20 min gradient from 70:30 B:A to 100%B, where A=90:10:0.1H₂O:MeOH:TFA and B=90:10:0.1 MeOH:H₂O:TFA) to give(120 mg; 30% over 2 steps) as a colorless oil. [M+H]⁺=543.2

EXAMPLE 475

Title compound was synthesized from Example 474 Part F compound (150 mg;1.0 mmol) and the carbamoyl chloride (440 mg; 1.0 mmol)

(prepared as described in Examples 6 and 139) followed by LiOH/H₂Ohydrolysis in the same manner as in Example 474. The title compound wasisolated and purified as a colorless oil (340 mg; 92% over 2 steps).[M+H]⁺=543.3

Following the procedures described above, the Examples 476 to 494compounds were prepared.

EXAMPLES 476 TO 484

Example No. R^(3h) [M + H]⁺ 476

519.1 477

535.1 478

579.1; 581.0 479

535.3 480

551.3 481

595.3; 597.3 482

529.3 483

527.3 484

543.4

EXAMPLES 485 TO 494

Example No. R^(3h) [M + H]⁺ 485

519.1 486

535.1 487

579.1; 581.0 488

535.3 489

551.3 490

595.2; 597.2 491

529.3 492

527.3 493

527.3 494

543.3

EXAMPLE 492

Example 492 was synthesized according to the procedures describedhereinbefore.

¹H NMR (CDCl₃; 400 MHz): δ 0.68 (t, J=4.4 Hz; 2H), 0.94 (t, J=4.4 Hz;2H), 1.87 (m, 1H), 2.42 (s, 3H), 3.06 (s, 2H), 4.02 (t, J=5.2 Hz, 2H),4.22 (t, J=5.2 Hz, 2H), 4.60 (2 peaks, 2H), 6.84-6.89 (m, 4H), 7.15-7.26(m, 4H), 7.40-7.47 (m, 3H), 7.98-8.00 (m, 2H).

The required (commercially unavailable) phenols and chloroformates forthe synthesis of the above carbamate-acid analogs were prepared asfollows:

3-Fluoro-4-methyl-phenyl chloroformate

A mixture of 5-methoxy-2-methyl aniline (5.0 g; 36 mmol), HCl (7.6 mL ofa 12 M solution; 91 mmol) and H₂O (11 mL) was heated at 60° C. for 15min until complete dissolution had occurred. The reaction was cooled to0° C. and an aqueous solution of NaNO₂ (2.5 g; 36 mmol) was addeddropwise (internal temperature<7° C.). The reaction was stirred at 0° C.for 30 min and a 0° C. solution of HBF₄ (5.3 mL of a 48% solution; 40mmol) was added cautiously. The reaction was stirred at 0° C. for 20min, and the resultant brown solid was filtered, washed with ice water(3×10 mL) and H₂O (2×10 mL). The solid was dried under high vacuum for20 h, then heated (heat gun) until evolution of BF₃ (white fumes) hadceased. The resulting brown oil was partitioned between EtOAc and H₂O.The organic phase was dried (Na₂SO₄), concentrated in vacuo anddistilled by Kugelrohr to give 3-fluoro-4-methyl anisole (1.6 g; 31%) asa colorless oil.

To a −70° C. solution of 3-fluoro-4-methyl anisole (1.62 g; 11.6 mmol)in CH₂Cl₂ (10 mL) was added dropwise BBr₃ (10 mL; 12 mmol). The reactionmixture was stirred at −70° C. for 10 min, then allowed to warm to 0° C.and stirred at 0° C. for 2 h. The reaction was allowed to warm to RT andconcentrated in vacuo and the residue was partitioned between H₂O andEtOAc. The organic phase was washed with H₂O, dried (Na₂SO₄) andconcentrated in vacuo to give 3-fluoro-4-methyl phenol (1.1 g; 75%) asan oil.

A solution of 3-fluoro-4-methyl phenol (1.1 g; 8.7 mmol), phosgene (5.9mL of a 1.93 M solution in toluene; 8.7 mmol), DMF (10 μL) andN,N-dimethylaniline (1.27 g; 8.7 mmol) in chlorobenzene (10 mL) in asealed tube was stirred at RT for 2 h, then at 80° C. for 2 h. Thereaction was cooled to RT, stirred for RT for 1 h, then was concentratedin vacuo. The residue was distilled by Kugelrohr to furnish3-fluoro-4-methyl phenyl chloroformate (800 mg; 49%) as a clear oil.

3-chloro-4-methyl phenyl chloroformate

3-chloro-4-methyl phenyl chloroformate (600 mg; 45% overall for 2 steps)was synthesized from 3-chloro-4-methyl anisole (1.0 g) using the sameroute (BBr₃-mediated methyl ether cleavage followed by treatment withphosgene) as above.

3-bromo-4-methyl-phenyl chloroformate

To a 0° C. mixture of 3-bromo-4-methyl aniline (5 g; 27 mmol) and H₂SO₄(5.5 mL of a 16 M solution) in H₂O (7.5 mL) was added dropwise asolution of aqueous NaNO₂ (1.93 g; 28 mmol in 7.5 mL H₂O). The reactionwas stirred at 0° C. for 30 min, then was heated at 50° C. for 2 h, thenwas cooled to RT and extracted with EtOAc (2×). The combined organicextracts were washed with H O, dried (Na₂SO₄) and concentrated in vacuoto give 3-bromo-4-methyl phenol (1.72 g; 34%) as an oil. This phenol wasconverted to 3-bromo-4-methyl phenyl chloroformate (1.9 g; 82%) usingthe same procedure (phosgene/dimethylaniline/heat) as for3-fluoro-4-methyl phenyl chloroformate above.

2-Methoxyphenyl chloroformate (1.5 g) and 3-methoxyphenyl chloroformate(1.5 g) were both synthesized in the same way as for 3-fluoro-4-methylphenyl chloroformate (phosgene/dimethylaniline/heat) from2-methoxyphenol (2 g) and 3-methoxyphenol (2 g) respectively.

3-chloro-4-methoxy phenol

To a 0° C. solution of 3-chloro-4-methoxy aniline (1.0 g; 6.4 mmol) in1:1H₂O:conc. H₂SO₄ (100 mL) was added very slowly a solution of NaNO₂(0.5 g; 7.6 mmol) in H₂O (10 mL). Thick yellow fumes were emitted, andthe black solution was then heated to reflux for 30 min. The mixture wasextracted with EtOAc (4×50 mL) and the combined extracts wereconcentrated in vacuo. The residue was chromatographed (SiO₂; 4:1hex:EtOAc) to obtain 3-chloro-4-methoxy phenol (300 mg; 30%) as a yellowoil.

3-Fluoro-4-methoxy-phenol

A solution of 3′-fluoro-4′-methoxyacetophenone (10 g; 59 mmol) andm-chloroperbenzoic acid (50% purity; 30 g; 89 mmol) in CH2Cl2 (300 mL)was stirred at RT overnight. The solution was washed with saturatedaqueous Na₂CO₃, then filtered through a pad of SiO₂ (CH₂Cl₂ as eluent)and finally chromatographed (SiO₂; hex:EtOAc 4:1) to give the crudeproduct (3′-fluoro-4′-methoxy phenyl acetate; 63 g). A solution of thiscrude material and LiOH.H₂O (5 g; 120 mmol) in MeOH:H₂O (100 mL of a 9:1mixture) was stirred at RT overnight. Volatiles were removed in vacuo,and the residue was partitioned between excess aqueous 1 M HCl and EtOAc(aqueous layer pH ˜3). The aqueous phase was extracted with EtOAc (2×).The combined organic extracts were dried (Na2SO4) and concentrated invacuo to give 3-fluoro-4-methoxy phenol (6.1 g; 72%) as an oil.

3-bromo-4-methoxy phenol (4.39 g; 47% for 2 steps) was synthesized usingthe exact analogous sequence starting from 3-bromo-4-methoxybenzaldehyde.

3-propyl phenol

A mixture of 3-iodoanisole (2 g; 8.5 mmol), trimethyl-silylacetylene(1.67 g; 17 mmol), CuI (32 mg; 0.17 mmol) and (Ph₃P)₂PdCl₂ (59 mg; 0.085mmol) in diethylamine (10 mL) was stirred at RT for 1 h. Volatiles wereremoved in vacuo, and the residue was partitioned between EtOAc andbrine. The organic phase was washed with brine (2×10 mL) and thenfiltered through a pad of SiO₂. Volatiles were removed in vacuo to givethe crude product (3-trimethylsilylethynyl anisole) as a light yellowoil. A solution of this crude product and tetrabutylammonium fluoride(6.6 g; 26 mmol) in THF (10 mL) was stirred at RT for 15 min. Volatileswere removed in vacuo and the residue was chromatographed (SiO₂; 9:1hex:EtOAc) to furnish Part A compound (1.0 g; 89%) as a yellow oil.

To a 0° C. solution of Part A compound (1.0 g; 7.6 mmol) in anhydrousTHF (5 mL) was added dropwise n-BuLi (4.5 mL of a 2.0 M solution inhexane; 9.1 mmol). The resulting yellow solution was stirred at 0° C.for 30 min. Methyl iodide (1.6 g; 11.4 mmol) was then added and thereaction was allowed to warm to RT and stirred at RT for 30 min.Volatiles were removed in vacuo and the residue was partitioned betweenaqueous 1N HCl and EtOAc. The aqueous phase was extracted with EtOAc(3×20 mL), and the combined organic extracts were dried (MgSO₄) andconcentrated in vacuo to give Part B compound (1.0 g; 92%) as a yellowoil.

A solution of Part B compound (1.0 g) in MeOH (5 mL) was stirred over10% Pd/C (10 mg) under an atmosphere of H² overnight. The catalyst wasremoved by filtration through a pad of Celite® and the filtrate wasconcentrated in vacuo to give Part C compound (1.0 g; 100%) as a yellowoil.

To a −78° C. solution of Part C compound (1.0 g; 6.6 mmol) in CH₂Cl₂ (10mL) was added BBr₃ (4.8 mL of a 1 M solution in CH₂Cl₂). The reactionwas allowed to warm to RT and was stirred at RT for 3 h, after which itwas cautiously partitioned between aqueous 1 M HCl and CH₂Cl₂. Theorganic phase was washed with aqueous NH₄Cl, dried (MgSO₄) andconcentrated in vacuo to give 3-propyl phenol (900 mg; 100%) as a yellowoil.

EXAMPLE 495

A mixture of benzoic acid (1.22 g; 10 mmol), methanesulfonyl chloride(1.15 g; 10 mmol), K₂CO₃ (5.52 g; 40 mmol) and benzyltriethylammoniumchloride (0.23 g; 1 mmol) in toluene was stirred at 80° C. for 2 h.Ethyl hydrazine acetate hydrochloride (1.55 g; 10 mmol) was then addedand the reaction was stirred for a further 30 min, then cooled to RT.Solids were filtered off and the filtrate was concentrated in vacuo. Theresidue was chromatographed (SiO₂; stepwise gradient from 3:1 to 1:1hexane:EtOAc) to give Part A compound (350 mg; 16%) as a white solid.

To a 0° C. solution of Part A compound (49 mg; 0.22 mmol) and thealdehyde (50 mg; 010 mmol)

in DCE (3 mL) was added NaBH(OAc)₃ (30 mg; 0.42 mmol). The reaction wasallowed to warm to RT and stirred at RT for 2 h, then at 60° C. for 18h. The mixture was cooled to RT and concentrated in vacuo. The residuewas purified by preparative HPLC (YMC S5 ODS 30×250 mm column; flowrate=25 mL/min; 20 min continuous gradient from 70:30 B:A to 100% B,where solvent A=90:10:0.1H₂O:MeOH:TFA and solvent B=90:10:0.1MeOH:H₂O:TFA) to give Part B compound.

A solution of crude Part B compound in THF (1 mL) and aqueous LiOH (0.3mL of a 1 M solution; 0.3 mmol) was stirred at RT for 3 h, thenacidified to pH ˜3 with aqueous 1 M HCl. The aqueous phase was extractedwith EtOAc (2×); the combined organic extracts were concentrated invacuo. The residue was purified by preparative HPC (YMC S5 ODS 30×250 mmcolumn; flow rate=25 mL/min; 22 min continuous gradient from 70:30 B:Ato 100% B, where solvent A=90:10:0.1H₂O:MeOH:TFA and solvent B=90:10:0.1MeOH:H₂O:TFA) to give title compound (26 mg; 33% yield over 2 steps) asa white solid. [M+H]⁺=486.3

EXAMPLE 496

To a 0° C. solution of the aldehyde (200 mg; 0.65 mmol)

in MeOH (2 mL) was added portionwise NaBH₄ (24 mg; 0.65 mmol), afterwhich the reaction was allowed warm to RT and stirred at RT for 1 h.Volatiles were removed in vacuo and the residue was partitioned betweenH₂O and EtOAc. The organic phase was dried (Na₂SO₄) and concentrated invacuo to give the intermediate alcohol as an oil. A solution of thealcohol in CH₂Cl₂ (2 mL) and PBr₃ (1 mL of a 1M solution in CH₂Cl₂) wasstirred at RT for 30 min. Volatiles were removed in vacuo and theresidue was partitioned between aqueous saturated NaHCO₃ and EtOAc. Theorganic phase was washed with H O, dried (Na₂SO₄) and concentrated invacuo to give Part A compound (150 mg; 62%) as an oil.

A solution of Part A compound (42 mg; 0.11 mmol), Example 500 Part Acompound (25 mg; 0.11 mmol) and K₂CO₃ (100 mg; 0.71 mmol) in DMF (1 mL)was stirred at RT for 3 days. The reaction mixture was partitionedbetween EtOAc and H₂O. The organic phase was washed with H₂O (2×) andconcentrated in vacuo. The residual oil was dissolved in THF (1 mL) andaqueous LiOH (0.3 mL of a 1 M solution) was added. The reaction wasstirred at RT for 3 h, then acidified to pH ˜3 with aqueous 1 M HCl. Theaqueous phase was extracted with EtOAc (2×); the combined organicextracts were concentrated in vacuo. The residue was purified bypreparative HPC (YMC S5 ODS 30×250 mm column; flow rate=25 mL/min; 20min continuous gradient from 70:30 B:A to 100% B, where solventA=90:10:0.1H₂O:MeOH:TFA and solvent B=90:10:0.1 MeOH:H₂O:TFA) to givetitle compound (15 mg; 27% yield over 2 steps) as a white solid.[M+H]⁺=486.4

EXAMPLE 497

A mixture of 3-hydroxyacetophenone (650 mg; 4.78 mmol), K₂CO₃ (660 mg;4.78 mmol) and the 2-phenyl-5-methyl-4-oxazole-ethanol mesylate (1.12 g;3.98 mmol)

in MeCN (40 mL) was refluxed overnight. Volatiles were removed in vacuo,and the residue was partitioned between EtOAc (100 mL) and 1.0 M aqueousNaOH (80 mL). The organic phase was washed with brine (100 mL), dried(MgSO₄) and concentrated in vacuo. The residue was chromatographed(SiO₂; hexane:EtOAc 3:1) to give Part A compound (850 g; 67%) as ayellow solid.

To a solution of Part A compound (850 mg, 2.65 mmol) in DCE (15 mL) weresuccessively added glycine methyl ester hydrochloride (333 mg, 2.65mmol), Et₃N (554 μL, 4.0 mmol), NaBH(OAc)₃ (786 mg; 3.7 mmol) and aceticacid (152 μL; 2.65 mmol). The reaction mixture was stirred at RT for 6days, then partitioned between aqueous 1 M NaOH and CH₂Cl₂. The aqueousphase was washed with H₂O, then concentrated in vacuo. The residue waspartitioned between EtOAc and 1 M aqueous HCl. The organic phase waswashed with brine, dried (MgSO₄) and concentrated in vacuo to giverecovered starting material (Part A compound). The pH of the aqueous HClphase was adjusted to 10 with excess solid NaOH. This aqueous phase wasextracted with EtOAc (60 mL). The organic extract was washed with brine(60 mL), dried (MgSO₄) and concentrated in vacuo to give the crude PartB compound (400 mg; 39%) as an oil, which was used in the next stepwithout further purification.

To a solution of Part B compound (29 mg; 0.074 mmol) in pyridine (1.0mL) were added 4-tolyl chloroformate (14 μL; 0.089 mmol) and DMAP (10mg). The solution was heated at 61° C. for 2 h, then cooled to RT andconcentrated in vacuo to give crude Part C compound (36 mg) as a syrup.

A solution of crude Part C compound (36 mg; 0.68 mmol) and LiOH. H₂O (12mg; 0.28 mmol) in THF:MeOH:H₂O (1 mL of a 1:1:1 solution) was stirred atRT for 2 h. Volatiles were removed in vacuo and the residue wasacidified to pH 2 with aqueous 1 M HCl, then extracted with EtOAc (3×40mL). The combined organic extracts were dried (Na₂SO₄) and concentratedin vacuo. The crude product was purified by preparative HPLC (YMC S5 ODS50×250 mm column; flow rate=25 mL/min; continuous 20 min gradient from70:30 B:A to 100% B, where A=90:10:0.1H₂O:MeOH:TFA and B=90:10:0.1MeOH:H₂O:TFA) to give title compound (28 mg; 72% over 2 steps) as awhite solid. [M+H]⁺=515.3

EXAMPLE 498

A solution of (S)-1-(4-methoxyphenyl)ethylamine (11.9 g, 79 mmol),methyl bromoacetate (11.5 g; 75 mmol) and Et₃N (12.6 mL; 90 mmol) in THF(156 mL) was stirred at RT for 15 h. The reaction was partitionedbetween EtOAc and H₂O. The organic phase was washed with brine, dried(MgSO₄), and concentrated in vacuo to give crude Part A compound, whichwas used in the next step without further purification.

To a 0° C. solution of the crude Part A compound from above in CH₂Cl₂(198 mL) was slowly added dropwise BBr₃ (12.0 mL; 127 mmol). Thereaction was stirred at 0° C. for 3 h, then poured cautiously into a 0°C. mixture of saturated aqueous NH₄Cl and EtOAc. The aqueous phase wasneutralized by slow addition of solid NaHCO₃, then extracted with EtOAc(2×). The combined organic extracts were washed with brine, dried(MgSO₄) and concentrated in vacuo to furnish Part B compound (7.29 g;44% over 2 steps).

To a solution of Part B compound (6.13 g; 29.3 mmol) in dioxane:H₂O (98mL of a 1:1 solution) were successively added NaHCO₃ (3.2 g; 38 mmol)and 4-methoxy-phenyl chloroformate (3.92 mL; 26.4 mmol). The reactionwas stirred at RT for 2 h, then partitioned between EtOAc and H₂O. Theorganic phase was washed with brine, dried (MgSO₄), and concentrated invacuo to give crude Part C compound (10.0 g; 95%).

To a solution of Part C compound in MeCN (59 mL) were successively addedK₂CO₃ (2.43 g; 17.6 mmol) and the mesylate (4.93 g; 17.6 mmol).

The reaction was heated at 90° C. for 20 h, then cooled to RT. Themixture was partitioned between EtOAc and H₂O. The organic phase waswashed with brine, dried (MgSO₄) and concentrated in vacuo. The residuewas chromatographed (SiO₂; stepwise gradient from 8:1 to 3:1 to 1:1hexane:EtOAc) to give Part D compound (3.4 g; 36%).

To a solution of Part D compound (3.4 g; 6.25 mmol) in THF:H₂O (31 mL ofa 2:1 solution) was added LiOH.H₂O (0.525 g; 125 mmol). The reaction wasstirred at RT overnight for 14 h. EtOAc was added and the solution wasacidified with 1 N HCl solution to pH ˜2. The organic phase was washedwith brine, dried (MgSO₄) and concentrated in vacuo. The residue waspurified by preparative HPLC (YMC S5 ODS 30×250 mm column; flow rate=25mL/min; 22 min continuous gradient from 70:30 B:A to 100% B, wheresolvent A=90:10:0.1H₂O:MeOH:TFA and solvent B=90:10:0.1 MeOH:H₂O:TFA;retention time=17.8 min) to give the title compound (2.1 g; 63% yield)as a white solid. [M+H]⁺=531.3; ¹H NMR (DMSO-d₆; 400 MHz): δ 1.50 (2d,J=6.6 Hz; 3H), 2.37 (s, 3H), 2.94 (t, J=7.0 Hz, 2H), 3.74 (s, 3H), 3.81(m; 2H), 4.21 (t, J=6.2 Hz, 2H), 5.36 (m, 1H), 6.93 (m, 6H), 7.28 (m,2H), 7.50 (m, 3H), 7.91 (m, 2H)

EXAMPLE 499

The synthesis of title compound was done using the identical sequencedescribed for Example 498 compound except that (R)-4-methoxy-α-methylbenzylamine was used instead of the (S) isomer. [M+H]⁺=531.3;

¹H NMR (DMSO-d₆; 400 MHz): δ 1.50 (2d, J=7.0 Hz; 3H), 2.37 (s, 3H), 2.94(t, J=6.6 Hz, 2H), 3.74 (s, 3H), 3.84 (m; 2H), 4.21 (t, J=6.6 Hz, 2H),5.35 (m, 1H), 6.93 (m, 6H), 7.29 (m, 2H), 7.50 (m, 3H), 7.91 (m, 2H)

Alternative Synthesis of Examples 498 and 499

EXAMPLE 498A

To a RT mixture of (S)-1-(4-methoxyphenyl)-ethylamine (5.45 g, 36 mmol)in THF (50 mL) and aqueous NaHCO₃ (6.05 g in 25 mL H₂O) was addeddropwise benzyl chloroformate (6.20 mL; 43 mmol). The reaction wasstirred at RT for 30 min; the organic phase was isolated andconcentrated in vacuo. The residue was partitioned between EtOAc and H₂O(100 mL each); the organic phase was washed with brine, dried (MgSO₄),and concentrated in vacuo to about 30 mL volume. An equivalent volume ofhexane (30 mL) was added and Part A compound (9.12 g; 89%) crystallizedas colorless needles.

To a −78° C. solution of Part A compound (2.50 g; 8.8 mmol) in anhydrousCH₂Cl₂ (11 mL) was added dropwise a solution of BBr₃ in CH₂Cl₂ (11.4 mLof a 1.0 M solution; 11.4 mmol) over 25 min. The reaction was allowed towarm to 0° C. and stirred at 0° C. for 6 h, then quenched carefully at−78° C. by dropwise addition of excess MeOH (6 mL). The solution wasallowed to warm to 0° C. and stirred at 0° C. for 5 min. The solutionwas partitioned between CH₂Cl₂ (60 mL) and H₂O (50 mL). The organicphase was washed successively with brine and 5% aqueous NaHCO₃ (50 mLeach), dried (MgSO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; stepwise gradient from 4:1 to 1:1 hex:EtOAc) tofurnish Part B compound (1.30 g; 63% yield based on 650 mg (26%) ofrecovered unreacted Part A compound) as a white solid.

A mixture of Part B compound (1.10 g; 4.1 mmol), K₂CO₃ (680 mg; 4.9mmol) and the mesylate (1.25 g; 4.4 mmol)

in MeCN (30 mL) was heated at 90° C. for 18 h, then cooled to RT.Volatiles were removed in vacuo, and the residue was partitioned betweenEtOAc and H₂O (100 mL each). The organic phase was washed with brine(100 mL), dried (MgSO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; stepwise gradient from 9:1 to 3:2 hexane:EtOAc)to give Part C compound (1.40 g; 78%) as a white solid.

A mixture of Part C compound (1.30 g; 2.85 mmol) and 10% palladium oncarbon (200 mg) in MeOH (50 mL) was stirred under an atmosphere of H₂(balloon) at RT for 2 h, at which point the reaction was complete byHPLC. The catalyst was filtered off through Celite® and the filtrate wasconcentrated in vacuo to give Part D compound (600 mg; 65%) as a whitesolid.

A solution of Part D compound (600 mg; 1.86 mmol), methyl bromoacetate(230 μL; 2.42 mmol) and Et₃N (337 μL; 2.42 mmol) in THF (10 mL) wasstirred at RT for 20 h. The reaction mixture was partitioned between H₂Oand EtOAc (60 mL) each. The organic phase was washed with brine, dried(MgSO₄) and concentrated in vacuo. The residue was chromatographed(SiO₂; stepwise gradient from hex:EtOAc 4:1 to 1:1) to furnish Part Ecompound (640 mg; 87%) as an oil.

A solution of Part E compound (600 mg; 1.52 mmol), 4-methoxyphenylchloroformate (271 μL; 1.82 mmol) and DMAP (30 mg; 0.25 mmol) inpyridine (10 mL) was heated at 70° C. for 2 h. Since starting materialstill remained at this point, additional 4-methoxyphenyl chloroformate(271 μL; 1.82 mmol) was added and the reaction was heated at 70° C. foran additional 1 h. Volatiles were removed in vacuo, and the residue waspartitioned between EtOAc (100 mL) and 1M aqueous HCl (60 mL). Theorganic phase was washed with brine, dried (MgSO₄), and concentrated invacuo. The residue was chromatographed (SiO₂; stepwise gradient fromhex:EtOAc 9:1 to 4:1) to furnish Part F compound (880 mg) as an oil.

To a solution of Part F compound (880 mg; 1.62 mmol) in THF:H₂O (22 mLof a 2:1 solution) was added LiOH.H₂O (203 mg; 4.86 mmol). The reactionwas stirred at RT for 18 h; then EtOAc (100 mL) was added and thesolution acidified with 1 N HCl solution to pH 2. The organic phase waswashed with water and brine (100 mL each), dried (MgSO₄) andconcentrated in vacuo. The residue was purified by preparative HPLC (YMCODS 30×250 mm column; flow rate=25 mL/min; 22 min continuous gradientfrom 70:30 B:A to 100% B+5 min hold-time at 100% B, where solventA=90:10:0.1H₂O:MeOH:TFA and solvent B=90:10:0.1 MeOH:H₂O:TFA; retentiontime=17.8 min) and then lyophilized from dioxane to give the titlecompound (665 g; 78%) as a white solid.

EXAMPLE 499A

The alternative synthesis of Example 499 was done using the identicalsequence described for Example 498A except that(R)-1-(4-methoxyphenyl)ethylamine was used instead of the (S) isomer.

Alternative Synthesis of Example 498 Part B Compound

A mixture of tert-butyldimethylsilyl chloride (357 mg; 2.36 mmol),(alternative) Example 498A Part B compound from above (535 mg; 1.97mmol) and imidazole (161 mg; 2.36 mmol) in DMF (5 mL) was stirred at RTfor 2 h. The reaction was partitioned between EtOAc (20 mL) and water(50 mL). The organic phase was washed with water (2×50 mL), dried(Na₂SO₄), and concentrated in vacuo. The residue was chromatographed(SiO₂; hex:EtOAc 3:1) to give Part A compound (320 mg; 42%) as an oil inaddition to recovered starting phenol (150 mg; 20%).

A mixture of Part A compound (320 mg; 0.83 mmol) and 10% palladium oncarbon (30 mg) in MeOH (30 mL) was stirred under an atmosphere of H₂(balloon) at RT for 1 h, at which point the reaction was complete byHPLC. The catalyst was filtered off through Celite® and the filtrate wasconcentrated in vacuo to give Part B compound (230 mg) as a white solidwhich was used in the next step without further purification.

A solution of Part B compound (230 mg), methyl bromoacetate (86 μL; 0.91mmol) and Et₃N (127 μL; 0.91 mmol) in THF (10 mL) was stirred at RT for15 h. The reaction mixture was partitioned between H O and EtOAc (30 mL)each. The organic phase was washed with brine, dried (MgSO₄) andconcentrated in vacuo. The residue was chromatographed (SiO₂; stepwisegradient from hex:EtOAc 9:1 to 1:1) to furnish Part C compound (177 mg;66% over 2 steps) as an oil.

EXAMPLE 498 Part B Compound

To a solution of Part C compound (177 mg; 0.55 mmol) in THF (5.5 mL) wasslowly added tetrabutylammonium fluoride (1.65 mL of a 1 M solution inTHF). The reaction was stirred at RT for 10 min, then partitionedbetween water and EtOAc. The organic phase was washed with brine, dried(MgSO₄) and concentrated in vacuo. The residue was purified bypreparative HPLC (YMC reverse phase ODS 20×100 mm column; flow rate=20mL/min; 10 min continuous gradient from 100% A to 100% B+10 minhold-time at 100% B, where solvent A=90:10:0.1H₂O:MeOH:TFA and solventB=90:10:0.1 MeOH:H₂O:TFA; retention time=2.6 min) to provide the titlecompound (97 mg; 84%).

EXAMPLE 500

A mixture of 4-hydroxyphenyl butyl ketone (2.50 g; 14.0 mmol), 2-phenyl5-methyl oxazole-4-ethanol mesylate (3.30 g; 11.7 mmol) and K₂CO₃ (1.94g; 14.0 mmol) in acetonitrile (50 mL) was refluxed under Ar for 18 h.Volatiles were removed in vacuo and the residue was partitioned betweenH₂O and EtOAc. The aqueous phase was extracted with EtOAc. The combinedorganic extracts were washed with aqueous 1M NaOH and H O, dried (MgSO₄)and concentrated in vacuo. The residue was chromatographed (SiO₂;stepwise gradient from 3:1 to 9:1 hex:EtOAc) to give Part A compound(3.42 g; 80%) as a white solid.

A mixture of Part A compound (3.42 g; 9.42 mmol), glycine methyl esterHCl salt (1.18 g; 9.42 mmol), Et₃N (1.97 mL; 14.1 mmol), NaBH(OAc)₃(2.80 g; 13.2 mmol) and HOAc (0.54 mL; 9.42 mmol) in DCE (20 mL) wasstirred at RT for 6 days. At this point the reaction was incomplete, butwas not progressing any further. The reaction was quenched withsaturated aqueous NaHCO₃ (6 mL), then concentrated in vacuo. The residuewas partitioned between saturated aqueous NaHCO₃ and EtOAc. The organicphase was washed with saturated aqueous NaHCO₃ and H₂O, then extractedwith 1M aqueous HCl (the unreacted starting material remained in theorganic phase). The aqueous phase was basified with NaOH, then extractedwith EtOAc. The organic phase was washed with H₂O and brine, dried(MgSO₄) and concentrated in vacuo to give Part B compound (365 mg; 9%)as an oil.

To a solution of Part C compound (50 mg; 0.11 mmol) in pyridine (1 mL)was added 4-methoxyphenyl chloroformate (40 μL) and DMAP (5 mg). Thereaction mixture was heated at 60° C. for 6 h, then was cooled to RT andvolatiles were removed in vacuo. The residue was dissolved inTHF/MeOH/H₂O (1 mL of a 2:2:1 mixture) and LiOH (30 mg) was added. Thereaction was stirred at RT for 18 h, then was acidified with aqueous 1 MHCl to pH˜2. The mixture was extracted with EtOAc (30 mL), washed withH₂O and brine (15 mL each), dried (MgSO₄) and concentrated in vacuo togive the crude product. This material was purified by preparative HPLC(YMC S5 ODS 30×250 mm column; continuous gradient from 60:40 A:B to 100%B over 30 min) to give, after lyophilization from MeOH/H₂O, the titlecompound (52 mg; 79%) as a white solid. [M+H]⁺=573.3

EXAMPLE 501

A mixture of glycine methyl ester hydrochloride (245 mg; 1.95 mmol),Et₃N (271 μL; 1.95 mmol) and the aldehyde

(400 mg; 1.3 mmol) and anhydrous MgSO₄ (200 mg) in THF (4 mL) wasstirred at RT overnight, then filtered. The filtrate was concentrated invacuo to give crude Part A compound, which was used in the next stepwithout further purification.

A mixture of indium metal (448 mg; 3.9 mmol) and allyl bromide (334 μL;3.9 mmol) in anhydrous DMF (2 mL) was stirred at 0° C. for 50 min. Asolution of the crude Part A compound (from above) in anhydrous DMF (2mL) was added to this mixture, and the reaction was stirred vigorouslyat RT for 3 h. Analytical HPLC/MS showed that the reaction was completeat this point. The reaction was partitioned between saturated aqueousNH₄Cl and EtOAc. The organic phase was washed with H₂O (an emulsionformed) and brine, dried (MgSO₄) and concentrated in vacuo to give crudePart B compound (300 mg; 55% for 2 steps). This material was used in thenext step without further purification.

To a 0° C. solution of Part B compound (150 mg; 0.36 mmol) and Et₃N (51μL; 0.36 mmol) in CH₂Cl₂ (4 mL) was added dropwise 4-methoxyphenylchloroformate (53 μL; 0.36 mmol). The reaction was allowed to warm to RTand stirred at RT for 1 h, then concentrated in vacuo. The residue waschromatographed (SiO₂; hexane:EtOAc 2:1) to give Part C compound (200mg; 98%) as an oil.

A solution of Part C compound (100 mg, 0.18 mmol) and LiOH.H₂O (30 mg,0.72 mmol) in THF:MeOH:H₂O (1 mL of a 1:1:1 solution) was stirred at RTfor 2 h. The reaction mixture was then acidified to pH ˜2 with aqueous1N HCl. The aqueous phase was extracted with EtOAc (2×). The combinedorganic extracts were dried (Na₂SO₄), concentrated in vacuo andlyophilized from dioxane to provide title compound (80 mg; 82%) as awhite solid. [M+H]⁺=557.2

EXAMPLE 502

A solution of Example 501 Part C compound (100 mg; 0.18 mmol) in MeOH(10 mL) in the presence of 10% Pd/C (50 mg) was stirred under an H₂atmosphere for 2 h at RT. The catalyst was then filtered off using a padof Celite®. The filtrate was concentrated in vacuo to give Part Acompound (100 mg; 100%) as an oil.

Title compound (87 mg; 90%; white solid lyophilate) was obtained fromPart A compound in the same way as Example 501 compound was synthesizedfrom Example 501 Part C compound. [M+H]⁺=559.2

EXAMPLE 503

To a solution of 5-methyl 2-phenyl-thiazol-4-yl-ethanol (50 mg; 0.23mmol) in CH₂Cl₂ (3 mL) were successively added Et₃N (50 μL; 0.36 mmol)and methanesulfonyl chloride (20 μL; 0.26 mmol). The reaction wasstirred at RT for 2 h, then was partitioned between CH₂Cl₂ and aqueous 1M HCl. The organic phase was washed with brine, dried (Na₂SO₄), andconcentrated in vacuo to give Part A compound (68 mg; 100%) as acolorless oil. This material was used in the next step without furtherpurification.

A mixture of the phenol (prepared using the identical procedures asdescribed for the synthesis of Example 498 Part C compound except thatethyl bromoacetate was used instead of methyl bromoacetate)

(18 mg; 0.048 mmol) and K₂CO₃ (30 mg; 0.22 mol) in MeCN (2 mL) washeated at 60° C. overnight, then cooled to RT and partitioned betweenEtOAc and excess aqueous 1 M HCl. The aqueous phase was extracted withEtOAc (2×); the combined organic extracts were dried (Na₂SO₄) andconcentrated in vacuo. The residue was purified by preparative HPLC (asdescribed for Example 498) to provide Part B compound (12 mg; 43%).

A solution of Part B compound (12 mg; 0.02 mmol) and LiOH.H₂O (10 mg;0.24 mmol) in THF (2 mL) and H₂O (1 mL) was stirred at RT for 4 h. Thereaction mixture was acidified with excess aqueous 1 M HCl and extractedwith EtOAc (3×). The combined organic extracts were dried (Na₂SO₄) andconcentrated in vacuo; the residue was purified by preparative HPLC (asdescribed for Example 498) to give the title compound (3 mg; 26%) as acolorless oil. [M+H]⁺=547.2

EXAMPLE 504

The title compound was prepared in exactly the same way as for Example503 except that the [S]-enantiomer

was used for the alkylation step. [M+H]⁺=547.2

EXAMPLE 505

To a solution of 1-(4-methoxyphenyl)-1-cyclopropane-carboxylic acid (250mg; 1.3 mmol) in dioxane (8 ml) were successively added Et₃N (198 μL;1.43 mmol) and diphenyl-phosphoryl azide (307 μL; 1.43 mmol). Thereaction was stirred at RT for 5 min, then heated to 80° C. for 3 h.Volatiles were removed in vacuo, and the residue was partitioned betweenEtOAc and H₂O. The organic phase was dried (Na₂SO₄) and concentrated invacuo to give the crude product (presumably the correspondingisocyanate). This material was dissolved in aqueous 8 M HCl (1.8 mL),stirred at RT for 5 min, then heated to 100° C. for 1 h. After coolingto RT, Et₂O was added, and the solution was cautiously basified withexcess solid NaOH. The aqueous phase was extracted with Et₂O (3×15 mL),dried (MgSO₄) and concentrated in vacuo to provide compound A (100 mg;47%) as an oil. This material was used in the next step without furtherpurification.

A solution of Part A Compound (100 mg; 0.61 mmol), methyl bromoacetate(103 mg; 0.67 mmol) and Et₃N (102 μL; 0.73 mmol) in THF was stirred atRT for 16 h. The reaction mixture was partitioned between EtOAc and H₂O.The organic phase was washed with brine, dried (MgSO₄), and concentratedin vacuo. The residue was chromatographed (SiO₂; CH₂Cl₂:MeOH 9:1) togive Part B compound (90 mg; 62%) as an oil.

To a 0° C. solution of Part B compound (90 mg; 0.38 mmol) in CH₂Cl₂(12.7 mL) was slowly added neat BBr₃ (82 μL; 0.87 mmol) The reaction wasstirred at 0° C. for 3 h, then was partitioned between ice coldsaturated aqueous NH₄Cl and EtOAc. The organic phase was discarded andthe aqueous layer was neutralized by addition of NaHCO₃, then extractedwith EtOAc (2×). The combined organic extracts were washed with brine,dried (MgSO₄), and concentrated in vacuo to give Part C compound (50 mg;59%).

A mixture of Part C compound (50 mg; 0.22 mmol), 4-methoxyphenylchloroformate (33 mg; 0.22 mol) and NaHCO₃ (25 mg; 0.29 mmol) in 1:1aqueous dioxane (7.5 mL) was stirred at RT for 2 h. The reaction mixturewas partitioned between EtOAc and H₂O. The organic phase was washed withbrine, dried (MgSO₄) and concentrated in vacuo to give Part D compound(45 mg; 52%).

A mixture of Part D compound (45 mg; 0.12 mmol), K₂CO₃ (30 mg; 0.22 mol)and the mesylate (33 mg; 0.12 mmol)

in MeCN (4 mL) was heated at 90° C. for 20 h. The reaction was cooled toRT and partitioned between EtOAc and H₂O. The aqueous phase wasextracted with EtOAc (2×); the combined organic extracts were dried(MgSO₄) and concentrated in vacuo. The residue was chromatographed(SiO₂; stepwise gradient from 9:1 to 1:1 hex:EtOAc) to provide Part Ecompound (42 mg; 65%).

A solution of Part E compound (42 mg; 0.08 mmol) and LiOH.H₂O (6 mg;0.15 mmol) in 2:1 THF:H₂O (3.8 mL) was stirred at RT overnight. Thereaction mixture was acidified to pH 2 with excess aqueous 1 M HCl andextracted with EtOAc (2×). The combined organic extracts were dried(Na₂SO₄) and concentrated in vacuo; the residue was purified bypreparative HPLC (as described for Example 498) to give the titlecompound (28 mg; 68%) as a colorless oil. [M+H]⁺=543.2

Following procedures as described above, the Examples 506 to 518compounds were prepared.

Example No. R^(a) [M + H]⁺ 506 (±) —Me 515.3 507 (±) n-Bu 557.4

Example No. R^(a) [M + H]⁺ 508 (±) Me 531.3 509 (±) Et 545.1 510 (±)i-Bu 573.3 511

571.3

EXAMPLE 506

¹H NMR (DMSO-d₆; 400 MHz): δ 1.47 and 1.54 (2d, J=7.5 Hz; 3H), 2.29 (s,3H), 2.37 (s, 3H), 2.93 (t, J=6.6 Hz, 2H), 3.81 (2d, J=18 Hz; 2H), 4.21(t, J=6.6 Hz, 2H), 5.3 (m, 1H), 6.94 (m, 4H), 7.18 (d, J=8.4 Hz, 2H),7.31 (m, 2H), 7.49 (m, 2H)

EXAMPLE 508

¹H NMR (DMSO-D₆; 400 MHz): δ 1.47 and 1.54 (2d, J=7.5 Hz; 3H), 2.37 (s,3H), 2.94 (t, J=6.6 Hz, 2H), 3.74 (s, 3H), 3.81 (m, 2H), 4.21 (t, J=6.6Hz, 2H), 5.36 (m, 1H), 6.94 (m, 4H), 7.29 (m, 2H), 7.49 (m, 3H), 7.91(m, 2H)

Example No. Structure [M + H]⁺ 512

531.3

The synthesis of Examples 513-518 involved the use of Example 541 Part Bcompound as the alkylating agent.

Example No. Structure [M + H]⁺ 513

517.2 514

517.2 515

501.2 516

501.2 517

517.2 518

517.2

EXAMPLE 519

A mixture of methyl α-aminoisobutyrate hydrochloride (108 mg; 0.7 mmol),Et₃N (146 μL; 111 mmol), NaBH(OAc)₃ (222 mg; 11 mmol) and the aldehyde(215 mg; 07 mmol)

in DCE (5 mL) was stirred at RT for 21 h. Some starting materialremained, so the reaction was heated at 55° C. for 4 h (no furtherreaction). Saturated aqueous NaHCO₃ was added, and volatiles wereremoved in vacuo. The residue was partitioned between H₂O and EtOAc. Theaqueous phase was extracted with EtOAc (2×). The combined organicextracts were washed with brine and extracted with aqueous 1 M HCl. Theaqueous phase was basified with solid NaOH and extracted with EtOAc(2×). The organic extracts were dried (Na₂SO₄) and concentrated in vacuoto give crude Part A compound (174 mg; 61%).

A solution of Part A compound (120 mg; 0.29 mmol) aqueous LiOH (2.0 mLof a 0.3 M solution of a 1:1:1 mixture of THF:MeOH:H₂O) was stirred atRT overnight. The reaction was acidified to pH ˜2 with aqueous 1 M HCl,then was concentrated in vacuo and purified by preparative HPLC (YMC S5ODS 30×250 mm column; flow rate=25 mL/min; continuous gradient from40:60 B:A to 100% B over 30 min, where solvent A=90:10:0.1H₂O:MeOH:TFA;solvent B=90:10:0.1 MeOH:H₂O:TFA) to furnish Part B compound (60 mg;53%) as a syrup.

A solution of Part B compound (25 mg; 0.06 mmol), 4-methoxyphenylchloroformate (20 μL) in pyridine (1 mL) was heated at 60° C. for 6 h.Volatiles were removed in vacuo and the residue was partitioned betweenEtOAc (2 mL) and aqueous 1 M HCl (1 mL). The organic phase wasconcentrated in vacuo and the residue was purified by preparative HPLC(YMC S5 ODS 30×250 mm column; flow rate=25 mL/min; continuous gradientfrom 40:60 B:A to 100% B over 20 min, where solvent A=90:10:0.1H₂O:MeOH:TFA; solvent B=90:10:0.1 MeOH:H₂O:TFA) to furnish title compound (4 mg;12%) as a white foam. [M+H]⁺=545.3

Following the procedures as set out hereinbefore, the following Examples520 to 535 compounds were prepared.

EXAMPLES 520 TO 535

Example No. Structure [M + H]⁺ 520

543.4 521

527.3 522

531.2 523

515.2 524

531.2 525

515.2 526

515.2

Example No. Structure [M + H]⁺ 527

543.3 528

527.3 529

545.3 530

531.2 531

515.2 532

515.2 533

531.2 534

515.2 535

515.2

EXAMPLE 536

To a 0° C. solution of (R)-(−)-lactate (3.0 g; 29 mmol) and Et₃N (4.8mL; 35 mmol) in CH₂Cl₂ (60 mL) was added methanesulfonyl chloride (2.67mL; 35 mmol). The mixture was stirred at 0° C. for 1 h, then partitionedbetween CH₂Cl₂ and 1M aqueous HCl (100 mL each). The organic phase waswashed with H₂O and brine, dried (MgSO₄), and concentrated in vacuowithout heating to give Part A compound as an oil (4.5 g; 86%), whichwas used in the next step without further purification.

A mixture of Part A compound (1.42 g; 6.0 mmol), (R)-4-methoxy-α-methylbenzylamine (300 mg, 2.0 mmol), and K₂CO₃ (828 mg; 6.0 mmol) in MeCN (20mL) was heated at 70° C. for 17 h (some amine starting material stillremained). The reaction cooled to RT, filtered, and the volatiles wereremoved in vacuo. The residue was partitioned between EtOAc and H O. Theorganic phase was washed with brine, dried (MgSO₄), and concentrated invacuo. The residue was chromatographed (SiO₂; stepwise gradient from99:1 to 97:3 CHCl₃:MeOH) to give Part B compound (330 mg; 70%) as anoil.

To a 0° C. solution of Part B compound (330 mg; 1.39 mmol) in CH₂Cl₂ (3mL) was slowly added dropwise BBr₃ (3.0 mL of a 1 M solution in CH₂Cl₂;30 mmol). The reaction was stirred at 10° C. for 3 h, then quenched bycautious addition of saturated aqueous NH₄C₁ and CH₂Cl₂. The isolatedaqueous phase was neutralized by slow addition of solid NaHCO₃, thenextracted with EtOAc (2×). The combined organic extracts were washedwith brine, dried (MgSO₄) and concentrated in vacuo to furnish crudePart C compound (150 mg; 48%), which was used in the next reactionwithout further purification.

To a solution of Part C compound (300 mg; 1.35 mmol) in dioxane:H₂O (6mL of a 1:1 solution) were successively added NaHCO₃ (500 mg; 5.95 mmol)and 4-methoxyphenyl chloroformate (300 μL; 2.0 mmol) slowly. Thereaction was stirred at RT for 1 h, then partitioned between EtOAc andH₂O. The organic phase was washed with brine, dried (MgSO₄), andconcentrated in vacuo to give a crude residue, which was chromatographed(SiO₂; stepwise gradient from 3:1 to 1:1 hexane:EtOAc) to furnish Part Dcompound (330 mg; 66%).

To a solution of Part D compound (330 mg; 0.88 mmol) in MeCN (20 mL)were successively added K₂CO₃ (165 mg; 1.2 mmol) and the mesylate (337mg; 1.2 mmol).

The reaction mixture was heated at 95° C. for 16 h, then cooled to RTand filtered. The filtrate was concentrated in vacuo and thenpartitioned between EtOAc and H₂O. The organic phase was washed withbrine, dried (MgSO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; 3:1 hexane:EtOAc) to give Part E compound (350mg; 71%).

To a solution of Part E compound (350 mg; 0.62 mmol) in THF:H₂O (15 mLof a 2:1 solution) was added LiOH.H₂O (52 mg; 1.2 mmol). The reactionwas stirred at RT overnight for 14 h; then EtOAc was added and thesolution acidified with 1 N HCl solution to pH ˜2. The organic phase waswashed with brine, dried (MgSO₄) and concentrated in vacuo. The residuewas purified by preparative HPLC (YMC S5 ODS 30×250 mm column; flowrate=25 mL/min; 20 min continuous gradient from 50:50 B:A to 100% B,where solvent A=90:10:0.1H₂O:MeOH:TFA and solvent B=90:10:0.1MeOH:H₂O:TFA; retention time=26 min) and lyophilized from dioxane togive the title compound (208 mg; 61% yield) as a white solid.[M+H]⁺=545.3

Alternative Synthesis of Example 536

A mixture of the phenol [500 mg; 1.94 mmol; prepared from(R)-1-(4-methoxyphenyl)ethylamine as for the alternative synthesis ofExample 498],

K₂CO₃ (400 mg; 2.89 mmol) and the mesylate (710 mg; 2.52 mmol)

in MeCN (6.5 mL) was heated at 90° C. in an oil bath under an atmosphereof Ar for 20 h. The reaction was allowed to cool to RT, diluted withCH₂Cl₂ (40 mL) and filtered. The filtrate was concentrated in vacuo. Theresidue was chromatographed (SiO₂; continuous gradient from 100% hex to4:1 hexane:EtOAc over 20 min, then 4:1 hex:EtOAc to 100% EtOAc over 20min, then EtOAc for 5 min) to furnish Part A compound (414 mg; 47%) as awhite solid.

A mixture of Part A compound (300 mg; 0.66 mmol) and 10% palladium oncarbon (50 mg) in MeOH (20 mL) was stirred under an atmosphere of H₂(balloon) at RT for 2 h, at which point the reaction was complete byHPLC. The reaction mixture was filtered through Celite® and the filtratewas concentrated in vacuo to provide Part B compound (208 mg; 79%) as anoil which eventually became a white solid upon standing.

A mixture of Part B compound (160 mg; 0.50 mmol), K₂CO₃ (206 mg; 1.49mmol) and the mesylate (292 mg; 1.49 mmol; Example 536 Part A compound)

in MeCN (5 mL) was heated at 70° C. for 24 h. At this point moremesylate (97 mg; 0.50 mmol) was added, and the reaction was heated at70° C. for a further 16 h. The reaction mixture was cooled to RT andfiltered. The filtrate was concentrated in vacuo, and the residue waschromatographed (SiO₂; stepwise gradient from hex:EtOAc 3:1 to 1:1) tofurnish Part C compound (98 mg; 47%) as an oil. This intermediate wasthen used for the preparation of Example 536 in an identical manner tothat previously shown.

EXAMPLES 537 TO 539

Following the procedures set out hereinbefore, the Examples 537 to 539compounds were prepared.

Example No. Structure [M + H]⁺ 537

545.3 538

545.3 539

545.3

EXAMPLE 540

To a 0° C. solution of 5-methyl-2-phenyl-oxazol-4-yl ethanol (5.0 g;24.6 mmol), acetone cyanohydrin (3.35 mL; 36.9 mmol) and Ph₃P (7.5 g;29.5 mmol) in THF (60 mL) was added DEAD (6.0 mL; 36.9 mmol) dropwise.After addition was complete, the reaction mixture was warmed to RT andstirred overnight at RT. Volatiles were removed in vacuo, and theresidue was chromatographed (SiO₂; hexane:EtOAc 2:1) to give Part Acompound (4.5 g; 86%) as an oil.

A solution of Part A compound (4.5 g; 21.2 mmol) and H₂SO₄(concentrated; 20 mL) in EtOH (100 mL) was heated under refluxovernight. The solution was concentrated in vacuo to ⅓ its originalvolume, then EtOAc (150 mL) and H₂O (100 mL) were cautiously added. Theorganic phase was washed with saturated aqueous NaHCO₃ (2×100 mL) andbrine (150 mL), dried (MgSO₄), and concentrated in vacuo to give a crudeoil. This material was chromatographed (SiO₂; hexane:EtOAc 2:1) to givePart B compound (2.1 g; 38%) as a crystalline solid.

To a −78° C. solution of Part B compound (2.1 g; 8.1 mmol) in THF (6 mL)was added dropwise LiAlH₄ (16 mL of a 1.0 M solution in THF; 16 mmol)under an atmosphere of N₂. The mixture was allowed to warm to 0° C. andstirred at 0° C. for 30 min, after which the reaction was determined tobe complete by TLC (hex:EtOAc 1:1). Aqueous HCl (1.0 mL of a 1 Msolution; 1 mmol) and saturated aqueous sodium potassium tartrate (10mL) were successively added and the mixture was stirred at RT for 30min. The mixture was extracted with EtOAc (100 mL), washed with H₂O andbrine, dried (Na₂SO₄) and concentrated in vacuo to give crude Part Ccompound (1.78 g; 97%) as a white solid, which was used in the next stepwithout further purification.

To a solution of Part C compound (670 mg; 3.09 mmol) and Et₃N (516 μL;3.71 mmol) in CH₂Cl₂ (4 mL) was added methanesulfonyl chloride (286 μL;3.71 mmol). The reaction mixture was stirred at RT for 30 min, at whichpoint the reaction was complete by TLC (hex:EtOAc 2:1). The mixture waspartitioned between CH₂Cl₂ (60 mL) and H₂O (40 mL). The organic phasewas washed with brine (40 mL), dried (MgSO₄), and concentrated in vacuoto give Part D compound (910 mg; 100%) which was used in the next stepwithout further purification.

A mixture of Part D compound (380 mg; 1.29 mmol), 4-hydroxybenzaldehyde(188 mg; 1.55 mmol) and K₂CO₃ (214 mg; 1.55 mg) in MeCN (12 mL) wasrefluxed in an oil bath for 17 h. At this point all starting Part Dcompound had been consumed (but there was a significant quantity of thehydrolysis by-product, Part C compound) by HPLC/MS. The reaction wascooled to RT and the solid precipitates were filtered off. The filtratewas concentrated in vacuo and partitioned between EtOAc (60 mL) and H₂O(40 mL). The organic phase was washed with brine (40 mL), dried (MgSO₄),and concentrated in vacuo to give the crude product. This material waschromatographed (SiO₂; stepwise gradient from 4:1 to 1:2 hex:EtOAc) togive Part E compound (150 mg; 36%) as an oil in addition to Part Ccompound (100 mg; 36%).

A mixture of Part E compound (150 mg; 0.50 mmol), glycine methyl esterhydrochloride (75 mg; 0.60 mmol) and Et₃N (84 μL; 0.60 mmol) in MeOH (5mL) was stirred at RT for 6 h, after which NaBH₄ (50 mg) was addedcautiously portionwise. The reaction mixture was stirred at RTovernight, after which volatiles were removed in vacuo. The residue waspartitioned between EtOAc and H O. The organic phase was washed withbrine, dried (Na₂SO₄) and concentrated in vacuo to give Part F compound(180 mg; 97%) as an oil.

A mixture of Part F compound (23 mg; 0.060 mmol), Et₃N (10 μL; 0.66mmol) and 4-tolyl chloroformate (10 μL; 0.066 mmol) in CH₂Cl₂ (1 mL) wasstirred at RT for 2 h. Volatiles were removed in vacuo and the residuewas dissolved in a solution of THF/MeOH/H₂O (1 mL of a 2:2:1 mixture);LiOH.H₂O (14 mg; 0.33 mmol) was added, and the reaction was stirred atRT for 2 h. Volatiles were removed in vacuo, and the residue waspartitioned between aqueous 1 M HCl and EtOAc. The organic extract wasconcentrated in vacuo and the residue was purified by preparative HPLC(YMC ODS S5 30 mm×250 mm column, continuous 25 minute gradient from 40%B:60% A to 100% B, hold at 100% B for 15 min, where solventA=90:10:0.1H₂O:MeOH:TFA and solvent B=90:10:0.1 MeOH:H₂O:TFA; flowrate=25 mL/min) to give the title compound as a white solid (13 mg; 45%over 2 steps). [M+H]⁺=515.3

EXAMPLE 541

To a solution of benzaldehyde (23.8 g, 234 mmol) in EtOAc (150 mL;pre-saturated with HCl gas) was added 2,3-butanedione mono-oxime (25.0g, 234 mmol) in one portion and the resulting solution was stirred at RTfor 12 h. Analytical HPLC indicated that all starting materials had beenconsumed. The reaction mixture was concentrated in vacuo to yield Part Acompound as a white solid, which was used in the next step withoutfurther purification.

To a solution of Part A compound in CHCl₃ (200 mL) was added dropwisePOCl₃ (30 mL, 320 mmol). The reaction was stirred for 12 h at 50° C.,then was concentrated in vacuo. The brown residue was partitionedbetween EtOAc (300 mL) and 1N aqeuous NaOH. The organic phase was washedwith brine, dried, (MgSO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; Et₂O) to give Part B compound (41.5 g; 86%) as alight brown solid (>95% pure by analytical HPLC and ¹H-NMR analysis).

A solution of 4-hydroxybenzaldehyde (20 g, 160 mmol), glycine methylester hydrochloride (22 g, 180 mmol) and Et₃N (25 mL, 180 mmol) in MeOH(200 mL) was stirred at RT for 12 h. The reaction mixture was cooled to0° C. and NaBH₄ (9.0 g, 240 mmol) was added portionwise whilemaintaining the reaction temperature at <RT. The reaction mixture wasstirred for 5 h, then was concentrated in vacuo to give crude Part Ccompound, which was used in the next step without further purification.

To a solution of crude Part C compound in Et₂O (300 mL) and H₂O (200 mL)were added NaHCO₃ (20 g, 240 mmol, in a single portion) and 4-tolylchloroformate (15 mL, 150 mmol; dropwise). The biphasic reaction mixturewas stirred for 12 h at RT. The aqueous phase was then extracted withEt₂O (2×200 mL). The combined organic extracts were washed with brine(2×50 mL), dried (MgSO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; stepwise gradient from 3:1 to 1:1 hexane:EtOAc)to give Part D compound (40.8 g; 76% over 2 steps) as an oil.

A solution of Part B compound (14.5 g, 70 mmol), Part C compound (21.6g, 67 mmol) and K₂CO₃ (18.4 g, 134 mmol) in CH₃CN (150 mL) was stirredat 80° C. for 12 h. The reaction was cooled to RT and volatiles wereremoved in vacuo. The brown oily residue was partitioned between EtOAc(250 mL) and brine (100 mL). The aqueous layer was extracted with EtOAc(3×100 mL). The combined organic extracts were dried (MgSO₄) andconcentrated in vacuo. The residue was chromatographed (SiO₂; stepwisegradient from 3:1 to 1:1 hexane:EtOAc) to give Part D compound (23.6 g;71%) as a colorless oil.

A solution of Part D compound (23.6 g, 47.4 mmol) and LiOH. H₂O (4.0 g,95 mmol) in THF (200 mL) and H₂O (120 mL) was stirred at RT for 4 h. Thereaction mixture was then acidified to pH ˜2 with aqueous 1N HCl. Theaqueous phase was extracted with EtOAc (3×200 mL). The combined organicextracts were dried (MgSO₄) and concentrated in vacuo to yield an oilyresidue, which was recrystallized from EtOAc to provide title compound(19.4 g; 84%) as a white solid. [M+H]⁺=487.23;

¹H NMR (CD₃OD; 400 MHz): δ 2.32 (s, 3H), 2.46 (s, 3H) 3.99 & 4.04 (2s,2H), 4.47 & 4.54 (2s, 2H), 5.01 and 5.00 (2s, 2H), 6.99 (d, J=8.4 Hz,2H), 7.05 (m, 2H), 7.17 (d, J=8.4 Hz, 2H), 7.31 (m, 2H); 7.49 (m, 3H),8.01 (m, 2H);

¹H NMR (CDCl₃; 400 MHz): δ 2.31 (s, 3H), 2.44 (s, 3H), 4.00 (s, 2H),4.55 (2s, 2H), 5.00 (2s, 2H); 6.99 (m, 4H); 7.13 (m, 2H), 7.21 (d, J=8.8Hz, 2H); 7.31 (m, 2H); 7.44 (s, 3H); 8.01 (s, 2H)

EXAMPLE 542

A mixture of 2-phenyl-5-methyl-oxazole-4-acetic acid (470 mg; 2.17 mmol;Maybridge) pyridine N-oxide (830 mg; 8.74 mmol) and acetic anhydride(350 mg; 3.57 mmol) in toluene (10 mL) was heated at 90° C. for 12 h,then concentrated in vacuo. The residue was then partitioned betweenEtOAc and 1M aqueous HCl. The organic phase was washed with saturatedaqueous NaHCO₃₁ brine, dried (Na₂SO₄) and concentrated in vacuo to givea dark brown oil. This material was chromatographed (SiO₂; 4:1hex:EtOAc) to give Part A compound (143 mg; 35%) as an oil.

To a 0° C. solution of Part A compound (600 mg; 3.21 mmol) and Ph₃P(3.37 g; 12.9 mmol) in CH₂Cl₂ (50 mL) was added dropwise a solution ofCBr₄ (2.13 g; 6.4 mmol) in CH₂Cl₂ (20 mL). The solution was stirred at0° C. for 2 h, then allowed to warm to RT and stirred at RT overnight.Volatiles were removed in vacuo and the residue was chromatographed(85:15 hexane:EtOAc) to furnish Part B compound (1.08 g; 98%) as a paleyellow solid. C.

To a −78° C. solution of Part B compound (1.12 g; 3.26 mmol) in THF (60mL) was added n-butyllithium dropwise (4.2 mL of a 1.6 M solution inhexane; 6.72 mmol) over 25 min, while maintaining the internaltemperature at ≦−71° C. The reaction was stirred at −78° C. for 1 h,then allowed to warm slowly to 0° C. Paraformaldehyde (305 g) was thenadded in one portion and the reaction was stirred at 0° C. for 3 h andthen quenched with saturated aqueous NH₄Cl. The aqueous phase wasextracted with EtOAc (2×); the combined organic extracts were washedwith brine, dried (Na₂SO₄) and concentrated in vacuo to give a dark oil.This material was chromatographed (SiO₂; 3:2 hex:EtOAc) to give Part Ccompound (466 mg; 67%) as a yellow solid.

To a 0° C. solution of Part C compound (466 mg; 2.19 mmol) and Et₃N inCH₂Cl₂ was added dropwise methanesulfonyl chloride (190 μL; 2.45 mmol)and the reaction was stirred at 0° C. for 1 h. The mixture was thenpartitioned between CH₂Cl₂ and cold 1M aqueous HCl. The organic phasewas washed with brine, dried (Na₂SO₄) and concentrated in vacuo. Thecrude product was chromatographed (SiO₂; 3:2 hex:EtOAc) to give Part Dcompound (533 mg; 84%) as an off-white solid.

A mixture of Part D compound (198 mg; 0.68 mmol), 4-hydroxybenzaldehyde(96 mg; 0.79 mmol) and K₂CO₃ (141 mg; 1.02 mmol) in CH₃CN (13 mL) washeated at 70° C. for 3 h, then stirred at RT overnight. Volatiles wereremoved in vacuo, and the residue was partitioned between EtOAc and 1 Maqueous NaOH. The organic phase was washed with brine, dried (Na₂SO₄)and concentrated in vacuo to give crude Part E compound (190 mg; 88%) asa yellow oil, which was used in the next step without furtherpurification.

A mixture of Part E compound (123 mg; 0.39 mmol), glycine methyl esterhydrochloride (248 mg; 1.98 mmol) and Et₃N (600 μL; 4.3 mmol) in DCE (15mL) was stirred at RT for 15 min, after which NaBH(OAc)₃H (262 mg; 1.2mmol) was added in one portion. The reaction was stirred for 16 h at RT,after which additional NaBH(OAc)₃H (200 mg; 0.94 mmol) was added.Stirring was continued for 3 h, after which still more NaBH(OAc)₃H (200mg; 0.94 mmol) was added. The reaction was stirred at RT for 48 h, afterwhich all Part E compound had been consumed. The reaction mixture waspartitioned between CH₂Cl₂ and aqueous NaHCO₃. The aqueous phase wasextracted with CH₂Cl₂ (2×). The combined organic extracts were washedwith brine, dried (Na₂SO₄) and concentrated in vacuo. The crude productwas chromatographed (SiO₂; stepwise gradient from 1:1 to 2:3 hex:EtOAc)to give Part F compound (120 mg; 79%) as a colorless oil whichsolidified on standing.

To a solution of Part F compound (180 mg; 0.46 mmol) and pyridine (100μL; 1.24 mmol) in CH₂Cl₂ (10 mL) was added 4-methoxyphenyl chloroformate(105 μL; 0.71 mmol). The reaction was stirred at RT for 3.5 h, thenpartitioned between aqueous NaHCO₃ and EtOAc. The aqueous phase wasextracted with EtOAc (2×). The combined organic extracts were washedwith brine, dried (Na₂SO₄) and concentrated in vacuo. The crude productwas chromatographed (SiO₂; hex:EtOAc 3:2) to give Part G compound (232mg; 93%) as a colorless oil.

To a solution of Part G compound (232 mg; 0.43 mmol) in THF:H₂O (12 mLof a 5:1 mixture) was added LiOH.H₂O (1.3 mmol). The solution wasstirred at RT overnight, then acidified with aqueous 1M HCl andextracted with EtOAc (2×). The combined organic extracts were washedwith brine, dried (Na₂SO₄) and concentrated in vacuo. The crude productwas purified by preparative HPLC (YMC S5 ODS 30×75 mm column, flowrate=20 mL/min; continuous gradient from 70:30 B:A to 100% B, wheresolvent A=90:10:0.1H₂O:MeOH:TFA and solvent B=90:10:0.1 MeOH:H₂O:TFA) togive title compound (160 mg; 71%) as a white solid. [M+H]⁺=527.2

EXAMPLE 543

A solution of 5-methyl-2-phenyloxazole-4-yl-acetic acid (4.0 g; 18 mmol)and concentrated HCl (2 mL) in MeOH (60 mL) was heated at refluxovernight. Volatiles were removed in vacuo; the residue was partitionedbetween H₂O and EtOAc. The organic phase was washed with brine, dried(MgSO₄) and concentrated in vacuo to give crude Part A compound as acolorless oil (4.00 g; 94%) which was used in the next step withoutfurther purification.

To a −78° C. solution of LDA (15.0 mL of a 2.0 M solution inheptane/THF; 30 mmol; Aldrich) were successively added dropwise asolution of Part A compound (2.3 g; 10 mmol) in THF (6 mL) and HMPA (500μL; 2.9 mmol). The solution was stirred at −78° C. for 30 min, afterwhich methyl iodide (1.87 mL; 30 mmol) was added dropwise. The solutionwas stirred at −78° C. for 1 h, then was allowed to warm to 0° C. andstirred at 0° C. for 1 h. The reaction solution was partitioned betweensaturated aqueous NH₄Cl and EtOAc. The aqueous phase was extracted withEtOAc (2×50 mL). The combined organic extracts were dried (MgSO₄) andconcentrated in vacuo to give crude Part B compound (1.90 g; 78%) as acolorless oil, which was used in the next step without furtherpurification.

To a −78° C. solution of LDA (7.0 mL of a 2.0 M in heptane/THF; 14 mmol;Aldrich) were successively added dropwise a solution of Part B compound(1.8 g; 7.3 mmol) in THF (5 mL) and HMPA (500 μL; 2.9 mmol). Thesolution was stirred at −78° C. for 1 h, then a solution of methyliodide (1 mL; 11 mmol) was added dropwise. The solution was stirred at−78° C. for 1 h, then was allowed to warm to 0° C. and stirred at 0° C.for 1 h. The reaction solution was then partitioned between saturatedaqueous NH₄Cl and EtOAc. The aqueous phase was extracted with EtOAc(2×50 mL). The combined organic extracts were dried (MgSO₄) andconcentrated in vacuo. The crude product was combined with the productfrom another reaction (from 670 mg of Part B compound) andchromatographed (SiO₂; 9:1 hexane:EtOAc) to give Part C compound (2.60g; 95%) as a colorless oil.

To a −78° C. solution of Part C compound (1.2 g; 4.63 mmol) in THF (3mL) under an atmosphere of N₂ was added dropwise a solution of LiAlH₄(1.0 mL of a 1.0 M solution in THF). The reaction was stirred at −78° C.for 1 h, then was allowed to warm to 0° C. and stirred at 0° C. for 30min. The reaction was quenched by cautious addition of 1M aqueouspotassium sodium tartrate followed by H₂O. The aqueous phase wasextracted with EtOAc. The combined organic extracts were washed with HO, dried (MgSO₄) and concentrated in vacuo to give crude Part D compound(1.01 g; 94%) as an oil, which was used in the next step without furtherpurification.

To an 80° C. solution of Part D compound (700 mg; 3.0 mmol), Ph₃P (1.2g; 4.6 mmol) and 4-hydroxybenzaldehyde (406 mg; 3.3 mmol) in THF (10 mL)was added DEAD (720 μL; mmol) in two portions over 5 min. The solutionwas stirred at 80° C. for 1 h (starting material still remained), thenwas concentrated in vacuo. The residue was chromatographed (SiO₂;stepwise gradient from 9:1 to 5:1 hexane:EtOAc) to give Part E compound(160 mg; 16%).

A solution of Part E compound (250 mg; 0.75 mmol), glycine methyl esterhydrochloride (141 mg; 1.13 mmol) and Et₃N (157 μL; 1.13 mmol) in MeOH(30 mL) was stirred at RT overnight. Excess solid NaBH₄ was addedcautiously; the reaction was stirred at RT for 1 h, then concentrated invacuo. The residue was partitioned between H O and EtOAc. The organicphase was washed with brine, dried (MgSO₄) and concentrated in vacuo togive crude Part F compound (300 mg; 98%) which was used in the nextreaction without further purification.

To a 0° C. solution of Part F compound (150 mg; 0.37 mmol) and Et₃N (51μL; 0.37 mmol) in CH₂Cl₂ (5 mL) was added 4-methoxyphenyl chloroformate(55 μL; 0.37 mmol). The reaction was allowed to warm to RT and stirredat RT for 2 h. Volatiles were removed in vacuo and the residue waschromatographed (SiO₂; 5:1 hexane:EtOAc) to furnish Part G compound (130mg; 63%).

A solution of Part G compound (130 mg) and LiOH. H₂O (39 mg) inH₂O/THF/MeOH (2 mL of a 1:2:2 mixture) was stirred at RT for 2 h.Volatiles were removed in vacuo, and the residue was acidified with 1.0M aqueous HCl, then extracted with EtOAc. The organic phase was dried(Na₂SO₄) and concentrated in vacuo to give a residue, which was purifiedby preparative HPLC (YMC S5 ODS reverse phase C18, 30×250 mm column;flow rate=25 mL/min; continuous gradient from 50% A:B to 100% B over 20min, where solvent A=90:10:0.1H₂O:MeOH:TFA, B=90:10:0.1 MeOH:H₂O:TFA),then lyophilized from dioxane to give the title compound (58 mg; 46%) asa white lyophilate. [M+H]⁺=545.4

EXAMPLE 544

Title compound was prepared in analogous fashion to Example 543 exceptthat 3-hydroxybenzaldehyde was used instead of 4-hydroxybenzaldehyde (inthe preparation of Example 543 Part E compound). [M+H]⁺=545.4

EXAMPLE 545

A mixture of the acetylene (38 mg; 0.065 mmol)

(synthesized in a completely analogous fashion to Example 542 Part Gcompound with glycine tert-butyl ester hydrochloride instead of glycinemethyl ester hydrochloride), quinoline (80 mg; 0.62 mmol) and Lindlar'scatalyst (8 mg; Pd/CaCO₃; Aldrich) in MeOH (8 mL) was stirred under anatmosphere of H₂ at 0° C. for 20 min. Additional Lindlar's catalyst (8mg; Pd/CaCO₃; Aldrich) was then added and stirring was continued underan atmosphere of H₂ at 0° C. for 25 min, after which reaction wascomplete. The mixture was filtered, and the filtrate was concentrated invacuo. The residue was purified by preparative HPLC (YMC S5 ODS 20×100mm column; flow rate=20 mL/min; continuous 20 min gradient from 80:20B:A to 100% B, where A=90:10:0.1H₂O:MeOH:TFA and B=90:10:0.1MeOH:H₂O:TFA) to give Part A compound (22 mg; 56%) as a colorless oil.

To a solution of Part A compound (3 mg; 0.005 mmol) in CH₂Cl₂ (0.5 mL)was added dropwise TFA (0.25 mL) and the reaction was stirred for 2 h atRT. Volatiles were removed in vacuo; the residue was dissolved in CDCl₃,filtered through a cotton plug and concentrated in vacuo to give thetitle compound (1.5 mg; 55%) as a colorless oil. [M+Na]⁺=551.0

Following procedures set out above, Examples 546 to 556 compounds wereprepared.

EXAMPLES 546 TO 556

Example No. Structure [M + H]⁺ 546

515.4 547

531.3 548

503.3 549

529.4 550

531.2 551

515.2

Example No. Structure [M + H]⁺ 552

531.3 553

487.3 554

503.3 555

527.2 556

511.4

EXAMPLE 555

A mixture of the mesylate (124 mg; 0.43 mmol),

3-hydroxybenzaldehyde (62 mg; 0.51 mmol) and K₂CO₃ (94 mg; 0.68 mmol) inCH₃CN (10 mL) were heated at 70° C. for 48 h. The reaction was cooled toRT, EtOAc was added, and the mixture was washed with aq 1M NaOH andbrine. The organic phase was dried (Na₂SO₄) and concentrated in vacuo.The residue was chromatographed (SiO₂; hex:EtOAc 4:1) to give Part Acompound (71 mg; 52%) as a colorless oil. [M+H]⁺=318.2

To a mixture of Part A compound (71 mg; 0.22 mmol), glycine.HCl (140 mg;1.11 mmol) and Et₃N (0.3 mL; 2.16 mmol) in 1,2 dichloroethane (10 mL)was added NaBH(OAc)₃ (150 mg). After stirring at RT for 16 h (reactionincomplete), more NaBH(OAc)₃ (150 mg) was added. A final addition ofNaBH(OAc)₃ (150 mg; in total 2.12 mmol) was made after another 3 h andthe reaction stirred for 48 h at RT. The reaction was complete at thispoint; saturated aqueous NaHCO₃ was added and the aqueous phase wasextracted with CH₂Cl₂ (2×). The combined organic extracts were washedwith brine, dried (Na₂SO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; hex:EtOAc=4:6) to give Part B compound (81 mg;93%) as a colorless oil.

To a solution of Part B compound (10 mg; 0.026 mmol) in CH₂Cl₂ (2 mL)were successively added pyridine (10 μL; 0.12 mmol) and 4-methoxyphenylchloroformate (10 μL; 0.067 mmol) (each in 0.1 mL CH₂Cl₂). The reactionwas stirred at RT for 16 h, then partitioned between aqueous 1N HCl andEtOAc. The organic phase was washed with brine, dried (Na₂SO₄), andconcentrated in vacuo. The residue was purified by preparative HPLC (YMCS5 ODS 30×75 mm column, flow rate=20 mL/min; continuous gradient from70:30 A:B to 100% B, where solvent A=90:10:0.1H₂O:MeOH:TFA and solventB=90:10:0.1 MeOH:H₂O:TFA) to give Part C compound (9 mg; 65%).

A solution of Part C compound (9 mg; 0.017 mmol) in 2:1 THF:H₂O (3 mL)was added LiOH (6 mg; 0.14 mmol). The solution was stirred at RT for 4h, then acidified with excess 1M HCl (aq). The solution was extractedwith EtOAc (2×5 mL). The combined organic extracts were washed withbrine, dried (Na₂SO₄), and concentrated in vacuo. The crude product waspurified by preparative HPLC using the same conditions as above to givetitle compound (6 mg; 68%) as a colorless film.

[M+H]⁺=527.2

EXAMPLE 556

Title compound was synthesized using the same sequence as Example 555compound from Example 555 Part B compound. Acylation with 4-methylchloroformate (67% after HPLC purification) followed by LiOH hydrolysisfurnished title compound (5 mg; 57% after HPLC purification).[M+H]⁺=511.4

EXAMPLE 557

A solution of 2-amino-5-cresol (5.0 g; 40 mmol), KOH (3.2 g; 57 mmol)was refluxed in EtOH (50 mL) and CS₂ (40 mL) for 8 h, after which thereaction mixture was concentrated in vacuo. The residue was partitionedbetween aq 1M HCl (100 mL) and EtOAc (200 mL). The organic phase waswashed with water (2×100 mL), dried (MgSO₄) and concentrated in vacuo togive Part A compound (4.0 g; 60%) as a white powder.

A solution of Part A compound (3.2 g; 19 mmol) and PCl5 (3.75 g; 19mmol) in toluene (150 mL) was heated at reflux for 2 h. The reactionmixture was washed successively with water and aqueous NaHCO₃, thendried (Na₂SO₄) and concentrated in vacuo to give Part B compound (4.0 g)as a crude oil. This material was used in the next step without furtherpurification.

A solution of the 1,3 benzyl glycine aminoester (150 mg; 0.39 mmol),Part B compound (100 mg; 0.59 mmol) and triethylamine (0.2 mL; 1.98mmol) in THF (5 mL) was heated at 100° C. in a sealed tube for 4 days.At this point LC/MS showed that all starting material had been consumed.Aqueous LiOH (0.5 mL of a 1 M solution) was added and the solution wasstirred at RT for 5 h. The mixture was concentrated in vacuo to give anoil, which was purified by preparative HPLC (as for Example 495) to givethe title compound (72 mg; 37%) as a solid.

EXAMPLE 558

A solution of the 1,4 benzyl glycine aminoester (50 mg; 0.13 mmol),Example 557 Part B compound (100 mg; 0.59 mmol) and triethylamine (0.2mL; 1.98 mmol) in THF (5 mL) was heated at 100° C. in a sealed tube for4 days. At this point LC/MS showed that all starting material had beenconsumed. Aqueous LiOH (0.5 mL of a 1 M solution) was added and thesolution was stirred at RT for 5 h. The mixture was concentrated invacuo to give an oil, which was purified by preparative HPLC (as forExample 495) to give the title compound (26 mg; 40%) as a solid.

EXAMPLE 559

To a solution of methyl propionylacetate (4.6 g, 35 mmol) in CHCl₃ (40mL) was added dropwise a solution of Br₂ (5.6 g; 35 mmol) in CHCL₃ (10mL) and the resulting mixture was stirred at 0° C. for 0.5 h. Thereaction was allowed to warm to RT and then air was bubbled into themixture for 1 h. Volatiles were then removed in vacuo to yield an oilyresidue, which was partitioned between EtOAc (100 mL) and saturatedaqueous NaHCO₃. The organic phase was washed with brine, dried (MgSO₄)and concentrated in vacuo to provide crude Part A compound (7.4 g, >95%yield; >90% purity) as an oil which was used in the next reactionwithout further purification.

A mixture of Part A compound (1.5 g, 7.2 mmol) and 4-methoxybenzamide(1.0 g, 6.6 mmol) was heated at 100° C. for 2.5 h. The reaction mixturewas chromatographed (SiO₂; 5% acetone/CH₂Cl₂) to yield Part B compound(0.57 g, 33%).

To a solution of the ester (0.57 g, 2.3 mmol) in THF (10 mL) was addedLiAH₄(2.5 mL of a 1 M solution in THF, 2.5 mmol) dropwise over 10 minand the reaction was stirred at RT for 0.5 h. The reaction was quenchedby adding a few drops of water and then partitioned between EtOAc (50mL) and brine (10 mL). The organic phase was dried (MgSO₄) andconcentrated in vacuo to give Part C (0.52 g, >95%) as an oil which wasused in the following reaction without further purification.

A mixture of Part C compound (0.52 g, 2.3 mmol), CH₃SO₂Cl (0.25 ml, 3.3mmol) and Et₃N (0.5 ml, 3.6 mmol) in CH₂Cl₂ (10 mL) was stirred at RTfor 12 h. Volatiles were removed in vacuo, and the residue waschromatographed (SiO₂; 4% acetone/CH₂Cl₂) to provide Part D compound(0.61 g, 85% for 2 steps) as a colorless oil.

To a mixture of crude Example 541 Part C compound (synthesized using4-hydroxybenzaldehyde [2.0 g; 16 mmol] and glycine methyl esterhydrochloride [2.3 g; 18 mmol]) in dioxane:H₂O (100 mL of a 1:1 mixture)were successively added NaHCO₃ (2.5 g; 30 mmol; in one portion) and4-methoxyphenyl chloroformate (2.0 mL; 14 mmol) dropwise. The reactionwas stirred at RT for 12 h and then extracted with EtOAc (4×150 mL). Thecombined organic extracts were dried (MgSO₄) and concentrated in vacuo.The residue was chromatographed (SiO₂; 3% acetone/CH₂Cl₂) to providePart E compound (2.4 g; 44%) as a colorless oil.

A mixture of Part E compound (86 mg, 0.25 mmol), Part D compound (60 mg,0.20 mmol) and K₂CO₃ (50 mg, 3.7 mmol) in DMF (3 mL) was heated at 80°C. for 12 h. The reaction was cooled to RT and filtered. Volatiles wereremoved in vacuo and the residue was chromatographed (SiO₂; 7:3hexane:EtOAc) to provide title compound (41 mg; 36%) as a colorless oil.

A solution of Part F compound (41 mg, 0.071 mmol) and LIOH.H₂O (34 mg;0.8 mmol) in THF—H₂O (2 mL of a 2:1 mixture) was stirred at RT for 2 h.The reaction mixture was acidified to pH ˜2 with 1 M aqueous HCl, thenwas extracted with EtOAc. The combined organic extracts wereconcentrated in vacuo and the residue was purified by preparative HPLC(YMC S5 ODS 30×250 mm column; flow rate=25 mL/min; 30 min continuousgradient from 50% A:50% B to 100% B, where solventA=90:10:0.1H₂O:MeOH:TFA and solvent B=90:10:0.1 MeOH:H₂O:TFA) to providetitle compound (17 mg, 40%) as a colorless oil. [M+H]⁺=547.23

EXAMPLE 560

A mixture of the mesylate (18 mg; 0061 mmol)

the ester,

[described in the synthesis of Example 503 Part B compound (50 mg; 0.13mmol)], K₂CO₃ (17 mg; 0.34 mmol) in CH₃CN (1 mL) were heated at 70° C.for 24 h. Additional K₂CO₃ (30 mg) and CH₃CN (1 mL) were added and themixture was heated at 75° C. for another 48 h. The reaction was cooledto RT, EtOAc was added, and the mixture was washed with aq 1M NaOH andbrine. The organic phase was dried (Na₂SO₄) and concentrated in vacuo togive the crude product. This was purified by preparative HPLC (YMC S5ODS 50×75 mm column; continuous gradient from 70:30 B:A to 100% B, whereA=90:10:0.1H₂O:MeOH:TFA and B=90:10:0.1 MeOH:H₂O:TFA) to give Part Acompound (13 mg; 35%) as a colorless oil.

To a solution of Part A compound (12 mg; 0.021 mmol) in 2:1 THF:H₂O (1.5mL) was added LiOH (8 mg; 0.19 mmol). The solution was stirred at RT for24 h, then acidified with excess 1M HCl (aq). The solution was extractedwith EtOAc (2×5 mL). The combined organic extracts were washed withbrine, dried (Na₂SO₄), and concentrated in vacuo. The crude product waspurified by preparative HPLC using the same conditions as above to givetitle compound (6.4 mg) as a colorless film. [M+H]⁺=541.3

EXAMPLE 561

A mixture of the mesylate (18 mg; 0061 mmol)

the phenol (50 mg; 0.13 mmol)

K₂CO₃ (17 mg; 0.34 mmol) in CH₃CN (1 mL) were heated at 70° C. for 24 h.Additional K₂CO₃ (30 mg) and CH₃CN (1 mL) were added and the mixture washeated at 75° C. for another 48 h. The reaction was cooled to RT, EtOAcwas added, and the mixture was washed with aq 1M NaOH and brine. Theorganic phase was dried (Na₂SO₄) and concentrated in vacuo to give thecrude product. This was purified by preparative HPLC (YMC 55 ODS 50×75mm column; continuous gradient from 70:30 B:A to 100% B, whereA=90:10:0.1H₂O:MeOH:TFA and B=90:10:0.1 MeOH:H₂O:TFA) to give Part Acompound (13 mg; 35%) as a colorless oil.

To a solution of Part A compound (12 mg; 0.021 mmol) in 2:1 THF:H₂O (1.5mL) was added LiOH (8 mg; 0.19 mmol). The solution was stirred at RT for24 h, then acidified with excess 1M HCl (aq). The solution was extractedwith EtOAc (2×5 mL). The combined organic extracts were washed withbrine, dried (Na₂SO₄), and concentrated in vacuo. The crude product waspurified by preparative HPLC using the same conditions as above to givetitle compound. [M+H]⁺=541.3

EXAMPLE 562

A solution of 4-iodobenzaldehyde (1.0 g; 4.31 mmol) and glycine methylester hydrochloride (0.65 g; 5.17 mmol) and Et₃N (0.50 g; 4.95 mmol) inMeOH (15 mL) was stirred at RT for 4 h. The mixture was cooled to 0° C.and a solution of NaBH₄ (230 mg; 6.0 mmol) in MeOH was addedportionwise. The mixture was allowed to warm to RT and stirred overnightat RT. Volatiles were removed in vacuo (without heating) and the residuewas partitioned between aq NaHCO₃ and EtOAc. The aqueous phase wasextracted with EtOAc (3×). The combined organic extracts were dried(Na₂SO₄) and concentrated in vacuo to give Part A compound as an oil.This material was used in the next step without further purification.

To a solution of the crude Part A compound and Et₃N (0.80 g; 8.00 mmol)in CH₂Cl₂ was added a solution of 4-methoxyphenyl chloroformate (0.93 g;5.00 mmol) in CH₂Cl₂. The reaction mixture was stirred at RT overnight,then partitioned between saturated aq NaHCO₃ and EtOAc. The aqueousphase was extracted with EtOAc (2×); the combined organic extracts weredried (Na₂SO₄) and concentrated in vacuo to give a residue, which waschromatographed (SiO₂; hex:EtOAc 3:1) to give Part B compound (1.2 g;61%) as an oil.

To a 0° C. solution of DL-propargyl glycine (3.0 g; 26.5 mmol) inpyridine (20 mL; 247 mmol) was added dropwise benzoyl chloride (3.73 g;26.5 mmol). The solution was allowed to warm to RT and stirred at RT for1 h. Acetic anhydride (10 mL) was added and the mixture was stirred at90° C. for 2 h. The reaction mixture was diluted with H₂O (35 mL) andextracted with EtOAc (3×); the combined organic extracts were washedwith aqueous 1N HCl, H₂O, aqueous NaHCO₃ and finally water. The organicphase was dried (Na₂SO₄) and concentrated in vacuo. The crude productwas chromatographed (SiO₂; stepwise gradient from 5:1 to 3:1 hex:EtOAc)to give Part C compound (1.0 g; 17%) as an orange solid.

A solution of Part C compound (1.0 g; 4.65 mmol), trifluoroaceticanhydride (3 mL) and TFA (3 mL) in a sealed tube was heated at 40° C.for 8 h. Volatiles were removed in vacuo and the residue was dissolvedin EtOAc (50 mL). The solution was washed repeatedly with saturated aqNaHCO₃ (until all acid had been removed from the organic phase), thenbrine, dried (Na₂SO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; 6:1 hex:EtOAc) to give Part D compound (800 mg;87%; >98% pure by HPLC) as an oil.

A mixture of Part D compound (100 mg; 0.507 mmol), Part B compound (254mg; 0.558 mmol), CuI (2 mg; 0.01 mmol) and (Ph₃P)₂PdCl₂ (4 mg; 0.005mmol) in diethylamine (2 mL) was stirred at RT for 3 h under N₂. At thispoint HPLC/MS showed that all starting material had been consumed andthe presence of a peak which corresponded to the desired product. Thereaction mixture was filtered and the filtrate was concentrated invacuo. The residue was chromatographed (SiO₂; stepwise gradient from 5:1to 2:1 hex:EtOAc) to provide Part E compound (200 mg; 75%) as an oil.

A solution of Part E compound (20 mg; 0.038 mol) in HOAc/conc HCl (1 mLof a 10:1 solution) was stirred at 45° C. overnight. Volatiles wereremoved in vacuo and the residue was purified by preparative HPLC (YMCS5 ODS reverse phase column; 30×250 mm; flow rate=25 mL/min; 30 mincontinuous gradient from 50:50 A:B to 100% B, where solvent A=90:10:0.1H₂O:MeOH:TFA and solvent B=90:10:0.1 MeOH:H₂O:TFA) to give the titlecompound (6.8 mg; 35%) as a lyophilate. [M+H]⁺=511.2

EXAMPLE 563

A solution of Example 562 Part E compound

(38 mg; 0.072 mmol) in MeOH (5 mL) was stirred under an atmosphere of H₂in the presence of 10% Pd/C catalyst (10 mg) at RT for 2 h. The catalystwas filtered off and the filtrate was concentrated in vacuo to give PartA compound (35 mg; 92%) as an oil.

A solution of Part A compound (35 mg; 0.066 mmol) in aqueous LiOH (1 mLof a 1M solution) and THF (5 mL) was stirred at RT for 2 h. The reactionwas acidified to pH 3 with excess aqueous 1M HCl and extracted withEtOAc (2×5 mL). The combined organic extracts were dried (Na₂SO₄) andconcentrated in vacuo. The residue was purified by preparative HPLC (YMCS5 ODS reverse phase column; 30×250 mm; flow rate=25 mL/min; 30 mincontinuous gradient from 50:50 A:B to 100% B, where solvent A=90:10:0.1H₂O:MeOH:TFA and solvent B=90:10:0.1 MeOH:H₂O:TFA) to give, afterlyophilization from dioxane, the title compound (31 mg; 87%) as a whitesolid. [M+H]⁺=515.9

EXAMPLE 564

A solution of Example 562 Part E compound

(20 mg; 0.038 mmol) and aqueous LiOH (1 mL of a 1 M solution; 1 mmol) inTHF (2 mL) was stirred at RT for 2 h. The reaction mixture was acidifiedwith excess aqueous 1 M HCl and extracted with EtOAc. The combinedorganic extracts were concentrated in vacuo. The residue was purified bypreparative HPLC ((YMC S5 ODS reverse phase column; 30×250 mm; flowrate=25 mL/min; 30 min continuous gradient from 50:50 A:B to 100% B,where solvent A=90:10:0.1 H₂O:MeOH:TFA and solvent B=90:10:0.1MeOH:H₂O:TFA) to give (9 mg; 46%) as a white solid. [M+H]⁺=511.2

EXAMPLE 565

A mixture of Example 562 Part E compound

(80 mg; 0.15 mmol), quinoline (2 μL; 0.01 mmol) and Lindlar's catalyst(7 mg; 5% Pd/CaCO₃) in toluene (2 mL) was stirred under an atmosphere ofH₂ for 2 h. More Lindlar's catalyst (20 mg) was then added and stirringwas continued under H₂ for another 2 h, after which the reaction wascomplete by analytical HPLC. The reaction mixture was filtered (Celite®)and the filtrate was concentrated in vacuo. The residue waschromatographed (SiO₂; stepwise gradient from 3:1 to 2:1 hexane:EtOAc)to give Part A compound.

A solution of Part A compound and aqueous LiOH (1 mL of a 1 M solution;1 mmol) in THF was stirred at RT overnight. The reaction mixture wasacidified with excess aqueous 1 M HCl and extracted with EtOAc (2×). Thecombined organic extracts were concentrated in vacuo. The residue waspurified by preparative HPLC (as for Example 495) to give the titlecompound (14 mg; 18%) as a white solid. [M+H]⁺=513.3

EXAMPLE 566 Racemic

To a 0° C. solution of Example 565 Part A compound

(60 mg; 0.11 mmol) in DCE (3 mL) was added dropwise diethylzinc (43 μL;0.29 mmol). The solution was stirred at 0° C. for 10 min andiodochloromethane (244 μL; 0.57 mmol) was then added. The reaction wasallowed to warm to RT and stirred at RT for 3 h, then was cautiouslyquenched by addition of aqueous HCl (1 mL of a 1 M solution). Theaqueous layer was extracted with EtOAc (2×); the combined organicextracts were dried (Na₂SO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; stepwise gradient from 3:1 to 2:1 hexane:EtOAc)to give crude Part A compound, which was used in the next step withoutfurther purification.

A solution of crude Part A compound and aqueous LiOH (1 mL of a 1 Msolution; 1 mmol) in THF was stirred at RT overnight. The reactionmixture was acidified with excess aqueous 1 M HCl and extracted withEtOAc. The combined organic extracts were concentrated in vacuo. Theresidue was purified by preparative HPLC (conditions) to give the titlecompound (7 mg; 12% over 2 steps) as a white solid. [M+H]⁺=527.2.

EXAMPLE 567

A mixture of Example 562 Part D compound

(300 mg; 1.52 mmol), N-bromo-succinimide (297 mg; 1.67 mmol) and AgNO₃(28 mg; 0.19 mmol) in acetone (2 mL) was stirred at RT for 30 min. Themixture was filtered and the filtrate was concentrated in vacuo. Theresidue was chromatographed (SiO₂; hexane:EtOAc 5:1) to give Part Acompound (320 mg; 76%) as yellow crystals.

To a solution of Part A compound (320 mg; 1.2 mmol), Ph₃P (13 mg; 0.05mmol) and Tris(dibenzylidene-acetone)dipalladium(0) (5 mg; 0.006 mmol)in THF (1 mL) was added Bu₃SnH (700 μL; 2.5 mmol) dropwise under anatmosphere of N₂. The mixture was stirred at RT for 2 h, then wasquenched by addition of aqueous KF (7 mL of a 1 M solution). The mixturewas stirred vigorously overnight, then extracted with EtOAc (2×). Thecombined organic extracts were washed with H₂O, dried (Na₂SO₄) andconcentrated in vacuo. The residual oil was chromatographed (SiO₂;hexane:EtOAc 3:1) to give Part B compound (200 mg; 35%) as an oil. Inaddition, the byproduct vinyl compound

(100 mg; 43%) was also obtained.

A solution of Part B compound (100 mg; 0.020 mmol) and Example 562 PartB compound

(100 mg; 0.22 mmol) and (Ph₃P)₄Pd^(o) (3 mg; 0.002 mmol) in toluene washeated at 100° C. overnight under an atmosphere of N₂. Volatiles wereremoved in vacuo and the residue was chromatographed (SiO₂; stepwisegradient from 3:1 to 2:1 hexane:EtOAc) to give Part C compound.

A solution of crude Part C compound (in aqueous LiOH (1 mL of a 1Msolution) and THF (5 mL) was stirred at RT overnight. The reaction wasacidified to pH 3 with excess aqueous 1 M HCl and extracted with EtOAc(2×5 mL). The combined organic extracts were dried (Na₂SO₄) andconcentrated in vacuo. The residue was purified by preparative HPLC (YMCS5 ODS reverse phase column; 30×250 mm; flow rate=25 mL/min; 30 mincontinuous gradient from 50:50 A:B to 100% B, where solvent A=90:10:0.1H₂O:MeOH:TFA and solvent B=90:10:0.1 MeOH:H₂O:TFA) to give, afterlyophilization from dioxane, title compound (23 mg; 20%) as a whitesolid. [M+H]⁺=513.3

EXAMPLES 568 TO 572

Following the procedures set out hereinbefore and in the workingExamples, the following compounds were prepared.

Example No. Structure [M + H]⁺ 568

511.2 569

515.9 570

511.2 571

513.2 572

513.3

EXAMPLE 573

To a mixture of the amino-ester (27 mg; 0.073 mmol)

5-methyl-2-phenyl-thiazol-4-yl-ethanol (25 mg; 0.11 mmol; Maybridge)resin-bound Ph₃P (27 mg; 0.081 mmol) in CH₂Cl₂ (0.5 mL) was added DEAD(20 μL; 0.13 mmol). The reaction was stirred at RT for 6 h, then wasfiltered. The filtrate was concentrated in vacuo and the residue waspurified by preparative HPLC (YMC S5 ODS 30×100 mm column; flow rate=50mL/min; continuous gradient from 30:70 B:A to 100% B, where solventA=90:10:0.1 H₂O:MeOH:TFA and solvent B=90:10:0.1 MeOH:H₂O:TFA) tofurnish Part A compound.

A solution of Part A compound in TFA (1 mL) was stirred at RT overnight,then was concentrated in vacuo to furnish title compound (11 mg; 26%) asa brown oil (94% purity by analytical HPLC). [M+H]⁺=517.2

EXAMPLE 574

To a mixture of the amino-ester (31 mg; 0.082 mmol)

5-methyl-2-phenyl-thiazol-4-yl-ethanol (25 mg; 0.11 mmol; Maybridge)resin-bound Ph₃P (32 mg; 0.096 mmol) in CH₂Cl₂ (0.5 mL) was added DEAD(20 μL; 0.13 mmol). The reaction was stirred at RT for 6 h, then wasfiltered. The filtrate was concentrated in vacuo to give crude Part Acompound.

A solution of crude Part A compound and LiOH.H₂O (20 mg; 0.48 mmol) inTHF:MeOH:H₂O (1 mL of a 3:1:1 mixture) was stirred at RT overnight. Thereaction was acidified to pH ˜4 with aqueous 1N HCl, then was extractedwith EtOAc (2×). The combined organic extracts were concentrated invacuo and the residue was purified by preparative HPLC (YMC S5 ODS30×100 mm column; flow rate=50 mL/min; 10 min continuous gradient from30:70 B:A to 100% B, where solvent A=90:10:0.1 H₂O:MeOH:TFA and solventB=90:10:0.1 MeOH:H₂O:TFA) to furnish title compound (16 mg; 34%) as abrown oil (95% purity by analytical HPLC). [M+H]⁺=565.2

EXAMPLE 575

To a solution of 2,4-dibromo-3-pentanone (Avocado Chemicals, 19.6 g, 80mmol) in CH₂Cl₂ (50 mL) was added dropwise Et₃N (30 mL, 210 mmol) over30 min; the resulting solution was heated to reflux for 12 h. Thereaction mixture was cooled to RT, then was poured into ice andacidified with concentrated HCl. The organic phase was concentrated invacuo to give an oil, which was fractionally distilled (b.p.=42°-45° C.at 13 mm Hg) to give Part A compound (6.0 g, 46%; with ˜20% of thestarting material) as an oil.

A mixture of Example 559 Part E compound (0.60 g, 1.7 mmol),

Part A compound (0.60 g, 3.7 mmol) and K₂CO₃ (1.0 g, 7.3 mmol) inbenzene (20 mL) was stirred at RT for 12 h. TLC at this point indicatedthat ˜50% of the starting material had been consumed and that thereaction had stalled. The reaction mixture was filtered and the filtratewas concentrated in vacuo. The residue was chromatographed (SiO₂; 3%acetone/CH₂Cl₂) to provide Part B compound (0.41 g; 47%) as an oil.

A solution of Part B compound (40 mg, 0.080 mmol) andthioisonicotinamide (50 mg, 0.36 mmol) in toluene-EtOH (3 mL of a 1:1mixture) was heated at 55° C. for 12 h. The reaction was cooled to RTand volatiles were removed in vacuo. The crude product was purified bypreparative HPLC (YMC S5 ODS 30×250 mm, continuous 30 min gradient from30% B:70% A to 100% B at 30 min, where solvent A=90:10:0.1 H₂O:MeOH:TFAand solvent B=90:10:0.1 MeOH:H₂O:TFA) to give Part C compound (17; 39%)as an oil.

A solution of Part C compound (17 mg, 0.031 mmol) and LiOH.H₂O (40 mg, 1mmol) in THF-H₂O (3 mL of a 2:1 mixture) was stirred at RT for 2 h. Thereaction mixture was acidified by addition of acetic acid and thenpartitioned between H₂O (2 mL) and EtOAc (5 mL). The organic phase wasdried (MgSO₄) and concentrated in vacuo to provide the title compound(13.7 mg, 81%) as a white solid. [M+H]³⁰ =534.2

EXAMPLES 576 TO 580

Following the procedures set out hereinbefore and in the workingExamples, the following compounds were prepared.

Example No. Structure [M + H]⁺ 576

551.2; 553.2 577

547.2 578

531.2 579

535.2; 537.2 580

551.2; 553.2

Examples 581 and 582 were synthesized according to the generalprocedures described for Examples 313 and 314.

Ex- am- [M + ple Structure H]⁺ 581

499.2 582

499.1

Examples 583 and 584 were synthesized according to the general methodsdescribed hereinbefore (e.g. for Example 139) using 4-methoxythiophenol.

Ex- am- [M + ple Structure H]⁺ 583

533.3 584

533.3

EXAMPLE 584

¹H NMR (CDCl₃; 400 MHz): δ 2.42 (s, 3H), 3.04 (br s; 2H), 3.79 (s, 3H),4.03 (br s, 2H), 4.25 (br s, 2H), 4.70 (br s, 2H), 6.8-7.0 (m, 5H),7.15-7.30 (m, 1H), 7.35-7.50 (m, 5H), 7.95-8.05 (m, 2H); 8.95 (br s, 1H)

EXAMPLE 585

To a −78° C. solution of methyltriphenylphosphonium bromide (4.2 g; 11.8mmol) in THF (60 mL) was added dropwise n-butyllithium (4.7 mL of a 2.5M solution in hexane; 11.8 mmol). The solution was allowed to warm to RTand stirred at RT for 45 min. To this mixture was added dropwise asolution of the aldehyde (3.0 g; 9.8 mmol)

in THF (15 mL). The reaction was stirred at RT for 30 min and at 50° C.for 13 h. After cooling to RT, the reaction mixture was partitionedbetween EtOAc and saturated aqueous NH₄Cl. The organic phase was washedwith brine, dried (MgSO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; Hexane:EtOAc; stepwise gradient from 9:1 to 4:1)to provide Part A compound (2.0 g; 67%).

To a solution of benzyl carbamate (3.07 g; 20.3 mmol) in n-propanol (26mL) was added a freshly prepared solution of aqueous NaOH (800 mg in 48mL H₂O) and tert-butyl hypochlorite (2.17 g; 20.0 mmol). After stirringat RT for 5 min, a solution of hydroquinidine 1,4-phthalazinediyldiether [(DHQD)₂PHAL; Aldrich; 256 mg; 0.33 mmol] in n-propanol (23 mL)was added, after which the mixture became homogeneous. A solution ofPart A compound (2.0 g; 6.56 mmol) in n-propanol (32 mL) was added,followed by a solution of potassium osmate dihydrate [K₂OsO₄(OH₂)₂; 97mg; 0.26 mmol] in aqueous NaOH (5 mL of a 0.4 M solution). The lightgreen reaction solution was stirred at RT for 30 min, after which itbecame yellow, and was cooled to 0° C. The reaction was quenched byaddition of saturated aqueous sodium sulfite (60 mL) and stirring for 15min. The aqueous phase was extracted with EtOAc (2×100 mL); the combinedorganic extracts were washed with water and brine, dried (MgSO₄) andconcentrated in vacuo. The residue was chromatographed (SiO₂; Hex:EtOAc;stepwise gradient from 9:1 to 1:1) to furnish Part B compound (1.80 g;58%) and the byproduct Part C compound (0.93 g; 30%).

To a 0° C. solution of Part B compound (1.10 g; 2.33 mmol) in CH₂Cl₂ (12mL) were successively added methanesulfonyl chloride (220 μL; 2.80 mmol)and Et₃N (420 μL; 3.03 mmol) dropwise. The reaction was stirred at 0° C.for 2 h, then was partitioned between CH₂Cl₂ and aqueous 1N HCl. Theorganic phase was washed with water and brine, dried (MgSO₄) andconcentrated in vacuo to provide Part D compound (1.10 g; 86%) as asolid.

A mixture of Part D compound (1.10 g; 2.0 mmol) and LiBr (260 mg; 3.0mmol) in acetone (4 mL) was heated at 50° C. for 14 h. The reaction wasthen cooled to RT and concentrated in vacuo. The residue waschromatographed (SiO₂; stepwise gradient from 9:1 to 4:1 hex:EtOAc) togive Part E compound (481 mg; 45%) as an oil.

To a −78° C. slurry of CuCN (17 mg; 0.19 mmol) in freshly distilledanhydrous THF (0.54 mL) was added dropwise n-butyllithium (150 μL of a2.5 M solution in hexanes). The mixture was allowed to warm slowly to 0°C. to generate the higher-order cuprate reagent as a clear tan solution.The reaction was then cooled to −50° C. and a solution of Part Ecompound (50 mg; 0.094 mmol) in THF (0.4 mL) was added dropwise. Thereaction was stirred at −50° C. for 1 h and then allowed to warm slowlyto 0° C. over 2 h. The mixture was then quenched at 0° C. by addition of9:1 saturated aqueous NH₄Cl:concentrated NH₄OH (2 mL), and then allowedto warm to RT with vigorous stirring until complete dissolution hadoccurred. The aqueous phase was extracted with EtOAc (2×), and thecombined organic extracts were washed with saturated aqueous NH₄Cl andbrine, dried (MgSO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; stepwise gradient from 9:1 to 2:1 hex:EtOAc) toprovide Part F compound (26 mg; 54%) as a solid.

A mixture of Part F compound (26 mg; 0.051 mmol) and 10% palladium oncarbon (10 mg) in 2:1 MeOH:EtOAc (1.2 mL) was stirred under anatmosphere of H₂ (balloon) at RT for 2 h, at which point the reactionwas complete by HPLC. The catalyst was filtered off through Celite® andthe filtrate was concentrated in vacuo to give Part G compound (18 mg;93%) as an oil.

A solution of Part G compound (18 mg; 0.048 mmol), methyl bromoacetate(9 μL; 0.095 mmol) and Et₃N (15 μL; 0.10 mmol) in THF (500 μL) wasstirred at RT for 15 h. The reaction mixture was partitioned between H Oand EtOAc (60 mL) each. The organic phase was washed with brine, dried(MgSO₄) and concentrated in vacuo to furnish crude Part H compound,which was used in the next step without further purification.

A solution of crude Part H compound, 4-methoxyphenyl chloroformate (21μL; 0.143 mmol) and 4-dimethyl-aminopyridine (4 mg; 0.033 mmol) inpyridine (10 mL) was heated at 70° C. for 2 h. The reaction mixture waspartitioned between EtOAc and 1M aqueous HCl. The organic phase waswashed with brine, dried (MgSO₄), and concentrated in vacuo. The residuewas purified by preparative HPLC (YMC reverse phase ODS 20×100 mmcolumn; 10 min continuous gradient from 50% A:50% B to 100% B+10 minhold-time at 100% B, where Solvent A=90:10:0.1 H₂O:MeOH:TFA, and SolventB=90:10:0.1 MeOH:H₂O:TFA; flow rate=20 mL/min; retention time=14.6 min)to furnish Part I compound (16 mg; 56% over 2 steps) as an oil.

To a solution of Part I compound (9.0 mg; 0.015 mmol) in THF:H₂O (750 μLof a 2:1 solution) was added LiOH.H₂O (2.5 mg; 0.06 mmol). The reactionwas stirred at RT for 15 h; then EtOAc (2 mL) was added and the solutionacidified with 1 N HCl solution to pH ˜2. The organic phase was washedwith water and brine, dried (MgSO₄) and concentrated in vacuo. Theresidue was purified by preparative HPLC (YMC reverse phase ODS 20×100mm column; flow rate=20 mL/min; 10 min continuous gradient from 50:50B:A to 100% B+10 min hold-time at 100% B, where solvent A=90:10:0.1H₂O:MeOH:TFA and solvent B=90:10:0.1 MeOH:H₂O:TFA; retention time=13.2min) to provide the title compound (6.0 mg; 68%) as a white solid.

[M+H]⁺=587.3

EXAMPLE 586

The synthesis of Example 586 was performed using the identical sequenceas described for Example 585 except that the catalyst used in theaminohydroxylation procedure (step 2) for the preparation of the keyintermediate

was hydroquinine 1,4-phthlazinediyl diether [(DHQ)₂PHAL; Aldrich]instead of hydroquinidine 1,4-phthlazinediyl diether [(DHQD)₂PHAL;Aldrich].

EXAMPLE 587

To a 0° C. solution of ethyl propionylacetate (10.0 g, 69.4 mmol) inCHCl₃ (60 mL) was added dropwise a solution of Br₂ (3.6 mL; 69.4 mmol)in CHCl₃ (20 mL) and the resulting mixture was stirred at 0° C. for 0.5h. The reaction was allowed to warm to RT and stirred at RT for 0.5 h.Air was then bubbled into the mixture for 1 h. Volatiles were thenremoved in vacuo to yield an oily residue to provide crude Part Acompound (15.3 g, >95% yield) as an oil which was used in the nextreaction without further purification.

To a mixture of piperonylic acid (2.0 g; 12 mmol), HOBT.H₂O (2.44 g;18.1 mmol) and NH₄Cl (1.28 g; 23.7 mmol) in DMF (48 mL) weresuccessively added EDCI.HCl (3.45 g; 18.1 mmol) and iPr₂NEt (2.3 mL; 48mmol). The reaction mixture was stirred at RT overnight until thestarting acid had been completely consumed (by HPLC). The mixture waspartitioned between H₂O (80 mL) and EtOAc (250 mL). The aqueous phasewas extracted with EtOAc (250 mL). The combined organic extracts werewashed with aqueous 1 N HCl (40 mL), dried (Na₂SO₄) and concentrated invacuo. The crude product was chromatographed (SiO₂; stepwise gradientfrom hex:EtOAc 1:1 to 100% EtOAc) to give Part B compound (1.5 g; 76%)as a white solid.

A mixture of Part A compound (2.11 g, 9.5 mmol) and Part B compound(1.41 g, 8.54 mmol) was heated with a heat gun until the mixture becamehomogeneous, after which the solution was heated at 130° C. in an oilbath for 5 h. The reaction mixture was chromatographed (SiO₂; continuousgradient from hex to 4:1 Hex:EtOac over 20 min, then continuous gradientfrom 4:1 Hex:EtOAc to 100% EtOAc over 15 min) to yield Part C compound(0.95 g, 39%) as a yellow solid.

To a −78° C. solution of Part C compound (0.95 g, 3.3 mmol) in anhydrousTHF (20 mL) was added LiAH₄(3.55 mL of a 1 M solution in THF, 3.55 mmol)dropwise over 10 min and the reaction was stirred at −78° C. for 0.5 h,then at 0° C. for 5 min. The reaction was quenched by sequentialcautious addition of water (0.13 mL), aqueous NaOH (20 mg in 0.13 mLH₂O) and water (0.20 mL). Anhydrous MgSO₄ (400 mg) was then added to themixture, which was stirred at RT for 10 min, then filtered. The filtratewas concentrated in vacuo and the residue was chromatographed (SiO₂;stepwise gradient from hex:EtOAc 1:1 to 100% EtOAc) to give Part Dcompound (350 mg; 43%) as an oil.

A mixture of Part D compound (0.35 g, 1.41 mmol), CH₃SO₂Cl (0.131 ml,1.69 mmol) and Et₃N (355 μL, 2.55 mmol) in anhydrous CH₂Cl₂ (6 mL) wasstirred at RT for 4 h, then partitioned between EtOAc (150 mL) and H₂O(10 mL). The organic phase was dried (MgSO₄) and concentrated in vacuo.The residue was chromatographed (SiO₂; stepwise gradient from hex:EtOAc1:1 to 100% EtOAc) to provide Part E compound (0.395 g, 86%) as a whitesolid.

A mixture of Part E compound (25 mg; 0.076 mmol), Example 559 Part Ecompound (25 mg, 0.073 mmol),

and K₂CO₃ (15 mg, 0.109 mmol) in acetonitrile (1 mL) was shaken andheated at 80° C. for 22 h. The reaction was cooled to RT and filtered.The filtrate was concentrated in vacuo and the residue was purified bypreparative HPLC (YMC reverse-phase ODS 20×100 mm column; continuousgradient over 10 min from 70:30 A:B to 100% B, where A=90:10:0.1H₂O:MeOH:TFA, and B=90:10:0.1 MeOH:H₂O:TFA, with 7 min hold time at 100%B; flow rate=20 mL/min) to provide Part F compound (21 mg; 51%) as acolorless oil.

A solution of Part F compound (21 mg, 0.037 mmol) and LiOH.H₂O (4.0 mg;0.095 mmol) in THF-H₂O (2.0 mL of a 1:1 mixture) was shaken at RT for 4h. The reaction mixture was acidified to pH 5 with 1 M aqueous HCl, thenwas extracted with EtOAc (3 mL) by shaking for 10 min. The organic phasewas washed with H₂O (2 mL) and concentrated in vacuo to provide Example586 (16.3 mg, 75%) as a solid foam.

[M+H]⁺=561.2

Examples 588 to 596 were prepared according to the scheme describedabove.

EXAMPLES 588 TO 591

Example No. Ar [M + H]⁺ 588

551.1 589

547.2 590

585.3 591

585.2

EXAMPLES 592 TO 596

Example No. Ar [M + H]⁺ 592

551.1 593

547.2 594

561.2 595

585.3 596

585.2

1. A compound having the structure

wherein PG in amino ester (a) and carbamoyl chloride (c) is a carboxylicacid protecting group, and

wherein X¹ _(x) is an alkylene chain of 1 to 4 carbons, an alkenylenechain of 2 to 4 carbons or an alkynylene chain of 2 to 4 carbons; X¹_(m) is an alkylene chain of 1 or 2 carbons, an alkenylene chain of 2carbons or an alkynylene chain of 2 carbons; X¹ _(n) is an alkylenechain of 1 or 2 carbons, an alkenylene chain of 2 carbons or analkynylene chain of 2 carbons; Q is C; A is O; R¹ is H or lower alkyl; Xis CH R² is H, alkyl, alkoxy, halogen, amino or substituted amino;R^(2a), R^(2b) and R^(2c) are the same or different and are selectedfrom H, alkyl alkoxy, halogen, amino or substituted amino; orstereoisomers thereof, or a pharmaceutically acceptable salt thereof. 2.The compound as defined in claim 1 wherein X¹ _(x) is CH₂, (CH₂)₂,(CH₂)₃, or

X¹ _(m) is CH₂, or

wherein R_(a) is alkyl or alkenyl, X¹ _(n), is CH₂, R¹ is lower alkyl,and R^(2a) H, X is CH; and PG is methyl, ethyl or t-butyl.
 3. Thecompound as defined in claim 1 having the structure

wherein PG is a carboxylic acid protecting group.
 4. A method forpreparing amino ester (a) having the structure

wherein X¹ _(x), is an alkylene chain of 1 to 4 carbons, an alkenylenechain of 2 to 4 carbons or an alkynylene chain of 2 to 4 carbons; X¹_(m) is an alkylene chain of 1 or 2 carbons, an alkenylene chain of 2carbons or an alkynylene chain of 2 carbons; X¹ _(n) is an alkylenechain of 1 or 2 carbons, an alkenylene chain of 2 carbons or analkynylene chain of 2 carbons; Q is C; A is O; R¹ is H or lower alkyl; Xis CH R² is H, alkyl, alkoxy, halogen, amino or substituted amino;R^(2a), R^(2b) and R^(2c) are the same or different and are selectedfrom H, alkyl, alkoxy, halogen, amino or substituted amino; and PG is acarboxylic acid protecting group; which comprises subjecting an aldehydeof the structure

to reductive amination by treating the aldehyde with an amino esterhydrochloride of the structure

to form amino ester (a).
 5. The method as defined in claim 4 whereinamino ester (a) has the structure

wherein PG is a carboxylic acid protecting group; the aldehyde has thestructure

and the amino ester hydrochloride has the structureCIH.H₂N CH₂CO₂PG wherein PG is a carboxylic acid protecting group.
 6. Amethod for preparing amino acid compound (b) which comprisesdeprotecting amino ester (a) which includes a carboxylic acid protectinggroup under PG basic conditions where PG is methyl or under acidicconditions where PG is t-butyl, to furnish amino acid (b), wherein saidamino acid (b) and amino ester (a) are defined in claim
 1. 7. The methodas defined in claim 6 wherein amino ester (a) has the structure

and amino acid compound (b) has the structure


8. A method for preparing carbamoyl chloride (c) as defined in claim 1which comprises treating amino ester (a) with phosgene (COCl)₂ to formcarbamoyl chloride (c).
 9. The method as defined in claim 8 whereinamino ester (a) has the structure

and carbamoyl chloride (c) has the structure